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Mitochondrial damage and associated oxidative stress are considered to be major contributory factors in cardiac pathology. One of the most potent naturally occurring antioxidants is taxifolin, especially in its water-soluble form. Herein, the effect of a 14-day course of the peroral application of the water-soluble taxifolin (aqTAX, 15 mg/kg of body weight) on the progression of ultrastructural and functional disorders in mitochondria and the heart's electrical activity in a rat model of myocardial injury induced with isoprenaline (ISO, 150 mg/kg/day for two consecutive days, subcut ) was studied. The delayed ISO-induced myocardial damage was accompanied by an increase in the duration of RR and QT intervals, and long-term application of aqTAX partially restored the disturbed intraventricular conduction. It was shown that the injections of ISO lead to profound ultrastructural alterations of myofibrils and mitochondria in cardiomyocytes in the left ventricle myocardium, including the impairment of the ordered arrangement of mitochondria between myofibrils as well as a decrease in the size and the number of these organelles per unit area. In addition, a reduction in the protein level of the subunits of the respiratory chain complexes I-V and the activity of the antioxidant enzymes catalase, glutathione peroxidase, and Mn-SOD in mitochondria was observed. The application of aqTAX caused an increase in the efficiency of oxidation phosphorylation and a partial restoration of the morphometric parameters of mitochondria in the heart tissue of animals with the experimental pathology. These beneficial effects of aqTAX are associated with the inhibition of lipid peroxidation and the normalization of the enzymatic activities of glutathione peroxidase and Mn-SOD in rat cardiac mitochondria, which may reduce the oxidative damage to the organelles. Taken together, these data allow one to consider this compound as a promising cardioprotector in the complex therapy of heart failure.

Isoproterenol (ISO) administration is a well-established model for inducing myocardial injury, replicating key features of human myocardial infarction (MI). The ensuing inflammatory response plays a pivotal role in the progression of adverse cardiac remodeling, characterized by myocardial dysfunction, fibrosis, and hypertrophy. The Mst1/Hippo signaling pathway, a critical regulator of cellular processes, has emerged as a potential therapeutic target in cardiovascular diseases. This study investigates the role of Mst1 in ISO-induced myocardial injury and explores its underlying mechanisms. Our findings demonstrate that Mst1 ablation in cardiomyocytes attenuates ISO-induced cardiac dysfunction, preserving cardiomyocyte viability and function. Mechanistically, Mst1 deletion inhibits cardiomyocyte apoptosis, oxidative stress, and calcium overload, key contributors to myocardial injury. Furthermore, Mst1 ablation mitigates endoplasmic reticulum (ER) stress and mitochondrial fission, both of which are implicated in ISO-mediated cardiac damage. Additionally, Mst1 plays a crucial role in modulating the inflammatory response following ISO treatment, as its deletion suppresses pro-inflammatory cytokine expression and neutrophil infiltration. To further investigate the molecular mechanisms underlying ISO-induced myocardial injury, we conducted a bioinformatics analysis using the GSE207581 dataset. GO and KEGG pathway enrichment analyses revealed significant enrichment of genes associated with DNA damage response, DNA repair, protein ubiquitination, chromatin organization, autophagy, cell cycle, mTOR signaling, FoxO signaling, ubiquitin-mediated proteolysis, and nucleocytoplasmic transport. These findings underscore the significance of Mst1 in ISO-induced myocardial injury and highlight its potential as a therapeutic target for mitigating adverse cardiac remodeling. Further investigation into the intricate mechanisms of Mst1 signaling may pave the way for novel therapeutic interventions for myocardial infarction and heart failure., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: Pathological cardiac remodelling, including cardiac hypertrophy and fibrosis, is a key pathological process in the development of heart failure. However, effective therapeutic approaches are limited. The β-adrenergic receptors are pivotal signalling molecules in regulating cardiac function. G-alpha interacting protein (GAIP)-interacting protein, C-terminus 1 (GIPC1) is a multifunctional scaffold protein that directly binds to the C-terminus of β1-adrenergic receptor (β1-adrenergic receptor). However, little is known about its roles in heart function. Therefore, we investigated the role of GIPC1 in cardiac remodelling and its underlying molecular mechanisms., Methods: Pathological cardiac remodelling in mice was established via intraperitoneal injection of isoprenaline for 14 d or transverse aortic constriction surgery for 8 weeks. Myh6-driving cardiomyocyte-specific GIPC1 conditional knockout (GIPC1 cKO) mice and adeno-associated virus 9 (AAV9)-mediated GIPC1 overexpression mice were used. The effect of GIPC1 on cardiac remodelling was assessed using echocardiographic, histological, and biochemical analyses., Results: GIPC1 expression was consistently reduced in the cardiac remodelling model. GIPC1 cKO mice exhibited spontaneous abnormalities, including cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, AAV9-mediated GIPC1 overexpression in the heart attenuated isoproterenol-induced pathological cardiac remodelling in mice. Mechanistically, GIPC1 interacted with the β1-adrenergic receptor and stabilised its expression by preventing its ubiquitination and degradation, maintaining the balance of β1-adrenergic receptor/β2-adrenergic receptor, and inhibiting hyperactivation of the mitogen-activated protein kinase signalling pathway., Conclusions: These results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The pyrimidine nucleoside uridine and its phosphorylated derivates have been shown to be involved in the systemic regulation of energy and redox balance and promote the regeneration of many tissues, including the myocardium, although the underlying mechanisms are not fully understood. Moreover, rearrangements in mitochondrial structure and function within cardiomyocytes are the predominant signs of myocardial injury. Accordingly, this study aimed to investigate whether uridine could alleviate acute myocardial injury induced by isoprenaline (ISO) exposure, a rat model of stress-induced cardiomyopathy, and to elucidate the mechanisms of its action related to mitochondrial dysfunction. For this purpose, a biochemical analysis of the relevant serum biomarkers and ECG monitoring were performed in combination with transmission electron microscopy and a comprehensive study of cardiac mitochondrial functions. The administration of ISO (150 mg/kg, twice with an interval of 24 h, s.c.) to rats caused myocardial degenerative changes, a sharp increase in the serum cardiospecific markers troponin I and the AST/ALT ratio, and a decline in the ATP level in the left ventricular myocardium. In parallel, alterations in the organization of sarcomeres with focal disorganization of myofibrils, and ultrastructural and morphological defects in mitochondria, including disturbances in the orientation and packing density of crista membranes, were detected. These malfunctions were improved by pretreatment with uridine (30 mg/kg, twice with an interval of 24 h, i.p.). Uridine also led to the normalization of the QT interval. Moreover, uridine effectively inhibited ISO-induced ROS overproduction and lipid peroxidation in rat heart mitochondria. The administration of uridine partially recovered the protein level of the respiratory chain complex V, along with the rates of ATP synthesis and mitochondrial potassium transport, suggesting the activation of the potassium cycle through the mitoK ATP channel. Taken together, these results indicate that uridine ameliorates acute ISO-induced myocardial injury and mitochondrial malfunction, which may be due to the activation of mitochondrial potassium recycling and a mild uncoupling leading to decreased ROS generation and oxidative damage.

Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae. The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway., (© 2023 John Wiley & Sons Ltd.)

The experimental myocardial infarction (MI) model originating from isoproterenol (ISO) is frequently preferred in research due to its similarity to MI-induced damage in humans. Beneficial effects of L-arginine (L-Arg), a semi-essential amino acid, in cardiovascular diseases have been shown in many studies. This study was carried out to determine whether L-Arg pre-intervention has protective effects on heart tissue in the experimental MI model. The 28 rats used in the study were randomly divided into 4 equal groups: control, L-Arg, ISO, and L-Arg+ISO. Upon completion of all applications, cardiac markers in serum and biochemical, histopathological, and immunohistochemical examinations in cardiac tissues were performed. Cardiac markers, histopathological changes, oxidative stress, inflammation, and apoptosis were increased in the experimental MI model. In addition, administration of ISO deregulated OTULIN levels and mitochondrial dynamics in heart tissue. However, L-Arg pre-intervention showed a significant protective effect against changes in ISO-induced MI. L-Arg supplementation with cardioprotective effect may reduce the risks of possible pathophysiological processes in MI., (© 2023. The Author(s), under exclusive licence to Cell Stress Society International.)

Background and Aims: The scientific community is concerned about cardiovascular disease mortality and morbidity, especially myocardial infarction (MI). Schisantherin A (SCA), a dibenzocyclooctadiene lignan monomer found in S. chinensis fruits has cardiovascular advantages such as increasing NO production in isolated rat thoracic aorta and reducing heart damage caused by ischemia-reperfusion (I/R) through decreasing apoptosis. The present study was undertaken to explore the potential effects of SCA on ISO-induced myocardial infarction in rats., Methods: Rats were randomly allocated to four groups: control; ISO-treated, and two additional groups of ISO + SCA (5 or 10 mg/kg body weight). All SCA-treated groups were administered with SCA for 20 days and all ISO groups were challenged with ISO on days 19 and 20., Results: SCA significantly attenuated ISO-induced rise in heart/body weight ratio, myocardial infarct size, and cardiac functional biomarkers (CK-MB, cTnI and BNP). SCA pre- and co-treatment resulted in a significant reduction in oxidative stress (via MDA, NO and GSH and increased activities of SOD, CAT and GPx) and inflammation (via decreased levels of TNF-α, IL-6 and IL-1β) markers when compared to the same levels in cardiac tissue of ISO-treated rats. This study also showed that SCA protects ISO-induced oxidative stress and inflammation by activating the PI3K-AKT/Nrf2/ARE pathway and suppressing TLR4/MAPK/NF-κB pathways. Furthermore, SCA treatment protected histopathological alterations observed in only ISO-treated cardiac transverse sections of rats., Conclusion: In conclusion, the findings of this study suggest that SCA protects against cardiac injury in the ISO-induced MI model of rats., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Cardiac hypertrophy is associated with increased translation. However, little is known of the mechanisms that regulate translation in hypertrophy. Members of the 2-oxoglutarate-dependent dioxygenase family regulate several aspects of gene expression, including translation. An important member of this family is OGFOD1. Here, we show OGFOD1 accumulates in failing human hearts. Upon OGFOD1 deletion, murine hearts showed transcriptomic and proteomic changes, with only 21 proteins and mRNAs (0.6%) changing in the same direction. Additionally, OGFOD1-KO mice were protected from induced hypertrophy, supporting a role for OGFOD1 in the cardiac response to chronic stress., (Published by Elsevier Ltd.)

Myocardial infarction (MI) is a major health problem associated with high morbidity and mortality. Recently, angiogenesis has emerged as a novel therapeutic approach against ischemic diseases including MI. Therefore, we aimed to investigate the potential angiogenic effects of vanillin (Van) both alone and in combination with pentoxifylline (PTX), and to examine the molecular mechanisms through which Van and PTX may ameliorate cardiac injury induced in rats including their effects on oxidative stress, inflammation and apoptosis which play a key role in MI pathogenesis. MI was induced in rats using isoproterenol (ISO) (150 mg kg -1 , SC, twice at a 24 h interval). Then, rats were treated orally with Van (150 mg kg -1 day -1 ), PTX (50 mg kg -1 day -1 ) or Van + PTX combination. ISO-induced cardiac injury was characterized by cardiac hypertrophy, ST-segment elevation and elevated serum levels of troponin-I, creatine kinase-MB and lactate dehydrogenase. Cardiac levels of the antioxidant markers GSH and SOD and the antiapoptotic protein Bcl-2 were decreased. On the other hand, cardiac levels of the oxidative stress marker malonaldehyde, the inflammatory cytokines TNF-α, IL-6 and IL-1β, the proapoptotic protein Bax, and caspase-3 were increased. Moreover, the cardiac levels of p-Akt and HIF-1α and the mRNA expression levels of the angiogenic genes VEGF , FGF-2 and ANGPT-1 were increased. Treatment with either Van or PTX ameliorated ISO-induced changes and further upregulated Akt/HIF-1α/VEGF signaling. Furthermore, Van + PTX combination was more effective than monotherapy. These findings suggest a novel therapeutic potential of Van and PTX in ameliorating MI through enhancing cardiac angiogenesis and modulating oxidative stress, inflammation and apoptosis.

Myocardial infarction (MI) is an instant ischemic death of cardiomyocytes that remains a major global cause of mortalities. MI is accompanied by oxidative, inflammatory, apoptotic, and fibrotic insults. Protocatechuic acid (PCA) is a polyphenolic compound with various potent biological activities. In this study, we explored the possible cardioprotective role of PCA against isoproterenol (ISO)-mediated MI. Rats were either injected with ISO (85 mg/kg, subcutaneously) or pretreated with PCA (100 or 200 mg/kg, orally). PCA supplementation markedly normalized ISO-induced disturbed cardiac function markers (creatine kinase-MB, lactate dehydrogenase, and troponin T). Notably, PCA administration exerted remarkable increases in glutathione and its derived enzymes, superoxide dismutase, and catalase, as well as decreases in malondialdehyde and nitric oxide levels in the injured cardiac tissue. The molecular findings validated the augmented cellular antioxidative capacity by PCA via increasing the gene expressions of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1. The cardioprotective efficacy of PCA extended to suppress cardiac inflammation as demonstrated by the decreased levels of tumor necrosis factor-alpha, interleukin-1 beta, and nuclear factor kappa B. Additionally, PCA prevented cardiomyocyte loss and fibrosis by decreasing Bax, caspase-3, transforming growth factor-β1 and matrix metalloproteinase-9, and enhancing B-cell lymphoma 2 and tissue inhibitors of metalloproteinase-3. The cardiac histological screening further confirmed the PCA's protective action. The obtained data recommend PCA as an alternative therapeutic agent to attenuate the molecular, biochemical, and histological alterations associated with MI development., (© 2023 Wiley Periodicals LLC.)

Background: The pharmacological mechanism of the traditional Chinese medicine formula-Jijiu Huiyang decoction (JJHYD), which contains several herbal medicines for the treatment of chronic heart failure (CHF), is yet unknown. Method and Materials . The main active components of JJHYD were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). The target genes of JJHYD and CHF were retrieved through multiple databases, a drug-ingredient-target-disease network was created, and KEGG enrichment and GO analyses were carried out. The binding ability of paeonol and Glycogen Synthase Kinase-3 alpha (GSK3A) was confirmed by molecular docking. CHF animal model and cell model were constructed. The effects of paeonol on cardiac dysfunction, myocardial hypertrophy, cardiac lipid accumulation, and myocardial apoptosis were detected by echocardiography, histopathology, and flow cytometry, respectively. The effects of paeonol on the expression of myocardial hypertrophy index, GSK3A, and genes or proteins related to the PPAR α pathway were determined by qRT-PCR or western blot., Result: UHPLC-MS/MS analysis combined with database verification showed a total of 227 chemical components in JJHYD, among which paeonol was the one with heart-protective roles and had the highest content. Paeonol alleviated isoproterenol-induced cardiac lipid accumulation, cardiac hypertrophy, and myocardial dysfunction and inhibited the activation of the PPAR α pathway, while overexpression of GSK3A reversed these effects of paeonol. However, the reversal effects of GSK3A overexpression could be offset by siPPAR α ., Conclusion: As the main active substance of JJHYD, paeonol participates in the protection of CHF by targeting the GSK3A/PPAR α signaling pathway to reduce lipid toxicity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wei Zhang et al.)

Scopoletin is a phenolic coumarin isolated from a variety of plants and was originally used to treat various diseases including arthritis as well as bone-related diseases. The goal of this study was to determine scopoletin's therapeutic potential in an animal model of myocardial infarction induced with ISO. There were five groups of albino male rats. Group I (control) animals were orally treated with olive oil. Group II (scopoletin) animals were pre-treated orally with a 50-mg dosage of scopoletin for 28 days. Group III (ISO-treated) animals were treated with 85 mg/kg of ISO subcutaneously for 2 consecutive days (29th and 30th day). Group IV (scopoletin and ISO) animals were pre-treated orally with 25 mg of scopoletin for 28 days before exposure to ISO. Group V (scopoletin and ISO) animals were pre-treated with 50 mg of scopoletin for 28 days before exposure to ISO. In the ISO-administered animals, a wider heart-to-body weight ratio, a higher heart weight, higher cardiac diagnostic markers, higher MDA levels and related antioxidant levels, inflammatory, and apoptotic markers were observed. Scopoletin pre-treatment with ISO (25 and 50 mg/kg b.wt) significantly reduced heart-to-body weight ratio, cardiac diagnostic markers, MDA, inflammatory markers, and apoptotic markers. Meantime, a pre-treatment with scopoletin increased the levels of antioxidant enzymes. Inflammation and necrosis were observed in the histopathology of heart tissue of ISO-treated animals and these histopathological conditions were reversed by scopoletin pretreatment. The antioxidant and anti-inflammatory properties of ISO-treated rats were shown to be increased by scopoletin, showing its therapeutic potential against cardiovascular diseases. Through the use of its antioxidant and anti-inflammatory properties, scopoletin exhibited anti-myocardial infarction properties. However, further preclinical studies will be required to demonstrate the mechanism of action of scopoletin involved in anti-myocardial infarction., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Myocardial infarction (MI) is among the main public health problems in the world. This atherosclerotic cardiovascular disease (ASCVD), which seriously endangers human health, progresses to cause heart failure and myocardial fibrosis with a poor prognosis. The gut microbiota plays an important role in health and disease, including obesity and ASCVD. In this study, the protective effect of Lacticaseibacillus rhamnosus GG, known for its anti-inflammatory and antioxidant effects, on isoprenaline (ISO)-induced MI in rats was investigated., Methods and Results: Rats were divided into four groups of seven rats in each group as control, ISO, L. rhamnosus, and ISO + L. rhamnosus.The ISO application was made by subcutaneous injection to the rats on the last two days (days 27th and 28th) of the 28-day substance administration. The rats were anesthetized 24 hours after the application of ISO, and blood samples were collected after electrocardiogram (ECG) recordings. To determine myocardial damage and protective effects of L. rhamnosus, serum creatine kinase-MB, cardiac troponin-I, tumor necrosis factor-alpha, interleukin-10, and C-reactive protein (CRP) levels were examined. In addition, ECG recordings were evaluated. While L. rhamnosus had a decreasing effect on cardiac troponin-I, creatine kinase-MB, CRP, and tumor necrosis factor-alpha levels, which increased due to ISO, it had an increasing effect on interleukin-10 levels. Similarly, it decreased the ST-segment elevation caused by ISO while increasing the reduced R wave amplitude., (© The Author(s) 2022. Published by Oxford University Press on behalf of Applied Microbiology International.)

Isoproterenol (ISO) is widely used to treat bronchial asthma, cardiogenic or septic shock, complete atrioventricular block, and cardiac arrest. However, it can also cause myocardial damage owing to infarct-like necrosis. Curdione, an extract of the Chinese herb Rhizoma Curcumae , has a variety of pharmacological activities, including cardioprotective effects. In this study, we investigated the protective effects of curdione and its underlying mechanisms in an ISO-induced myocardial injury model. Our results showed that curdione attenuated ISO-induced H9c2 cell proliferation inhibition and lactic dehydrogenase (LDH) release. Curdione ameliorated morphological damage and reduced the ISO-induced elevation of serum creatine kinase-MB isoenzyme (CK-MB) and LDH. Furthermore, curdione inhibited ISO-induced cell apoptosis, modulated the expression of Bcl-2 and Bax proteins, repealed the accumulation of ISO-induced reactive oxygen species (ROS), prevented mitochondrial dysfunction, and activated the Nrf2/SOD1/HO-1 signaling pathway. The above results show that curdione exerts a protective effect against ISO-induced myocardial damage by inhibiting apoptosis and oxidative stress, suggesting that curdione is a potential therapeutic strategy to prevent ISO-induced myocardial damage.

Objective: To investigate whether peroxisome proliferator-activated receptor γ-coactivator-1α/nuclear respiratory factor 1 (PGC-1α/NRF1) activity can protect mitochondrial function in the setting of cardiac hypertrophy and improve cardiomyocyte energy metabolism., Methods: Cardiac hypertrophy was modeled in H9c2 cells treated with isoproterenol (ISO) to assess the effects of Shenge San (, SGS) on cell viability and mitochondrial membrane potential. We assessed mitochondrial complex mRNA levels and mitochondrial oxidative phosphorylation factor mRNA and protein levels., Results: Compared with the 100 μM ISO group, cell size was significantly decreased in the 0.3 mg/mL SGS and 20 μM ZLN005 (PGC-1α activator) groups ( < 0.01). Compared with the SGS (0.3) +ISO group, we observed lower phosphorylated adenosine monophosphate-activated kinase (AMPK) protein levels in the ISO and ZLN005+SGS+ISO groups ( < 0.01). Compared with the compound C group, SGS significantly increased PGC-1α expression in ISO-induced cardiac hypertrophy cells ( < 0.01), and this was inhibited by compound C pretreatment ( < 0.05). Compared with the ISO group, the mitochondrial red-green fluorescence ratio increased in the 0.3 mg/mL SGS group ( < 0.05). mRNA levels of cytochrome c oxidase subunit 1 (CO1) in the ISO and compound C groups were lower than those in control group ( 0.01), and the mRNA levels of CO1 and ATP8 were significantly lower in the ISO and compound C groups versus control ( 0.01). Compared with the SGS (0.3) +ISO group, ATP synthetase subunit 8 (ATP8) mRNA was significantly decreased in the ISO group ( < 0.01) and compound C+SGS+ISO group ( < 0.05). Compared with the SGS (0.3) +ISO group, NRF1 mRNA levels were significantly decreased ( < 0.05) in the ISO and compound C+SGS+ISO groups., Conclusions: SGS can attenuate ISO-induced cardiomyocyte hypertrophy, restore the decrease in mitochondrial membrane potential, and upregulate PGC-1α/NRF1 levels. Notably, these effects can be blocked by AMPK inhibitor-compound C.

Qishen granules (QSG), a Chinese herbal formula, has been widely used in the treatment of myocardial ischemic chronic heart failure (CHF) for many years, but its mechanism of action is still unclear. In this study, comprehensive metabolomics was used to investigate the underlying protective mechanisms of QSG in an isoproterenol-induced CHF rat model. A total of 14 biomarkers were identified in serum and 34 biomarkers in urine, which were mainly related to fatty acid metabolism, bile acid metabolism, amino acid metabolism, purine metabolism, vitamin metabolism, and inflammation. Finally, 22 markers were selected for quantitative analysis of serum, urine, and fecal samples to verify the reliability of the results of untargeted metabolomics, and the results were similar to those of untargeted metabolomics. The correlation analysis showed that the targeted quantitative endogenous metabolites and CHF-related indexes were closely related. QSG might alleviate myocardial inflammatory response, oxidative stress, and amino acid metabolism disorder in CHF by regulating the level of endogenous metabolites. This study revealed QSG could regulate potential biomarkers and correlated metabolic pathway, which provided support for the further application of QSG., (© 2022 John Wiley & Sons Ltd.)

The present study investigated the cardioprotection of Indole-3-carbinol on isoproterenol (ISO)-induced myocardial infarction in Wistar rats. I3C treatment significantly reduced the prolongation of the QRS complex, QT interval, and ST-segment elevation. I3C was also able to normalise blood pressure (SBP, DBP, and MAP) and HR. I3C significantly decreased heart weight, cardiac troponin I (cTn I), CK-MB, LDH, AST and ALT. I3C ameliorated acute hyperglycaemia, hyperlipidemia, and myocardial infarction (%) in ISO rats. I3C treatment significantly elevated the antioxidant enzymes like SOD, CAT, and GSH and attenuated the MDA levels. I3C reduced the inflammatory cytokines (TNF-α and IL-6) and increased the anti-inflammatory cytokine 1 L-10. Furthermore, I3C significantly recovered myocardial structure by inhibiting neutrophil infiltration and oedema. Moreover, I3C attenuated apoptotic markers (cytochrome C, caspase 9 and caspase 3). Consequently, I3C restored cardiac function in MI rats by alleviating oxidative stress, inflammation, and apoptosis, and I3C could be used to treat myocardial infarction.

Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E'-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Hypertrophic cardiomyopathy is a major cause of mortality worldwide. In this study, we hypothesized that the combination of Dantrolene and Polymyxin-B will provide cardioprotective action against isoproterenol-induced hypertrophic cardiomyopathy via attenuation of Calmodulin-dependent protein kinase II (CaMKII). Hypertrophic cardiomyopathy was induced in rats by subcutaneous administration of isoproterenol (5 mg/kg) for 14 days. Simultaneously, animals were treated with Polymyxin-B per se, Dantrolene per se, and Dantrolene and Polymyxin-B combination for 14 days. Hemodynamic parameters, biochemical parameters, and histological analysis were performed. Administration of isoproterenol for 14 days resulted in severe myocardial damage, characterized by cardiac hypertrophy and increase serum CK-MB, CK-Nac, LDH, AST, and ALT levels. It also caused alteration in electrocardiogram and blood pressure. A significant increase in CaMKII was observed in heart homogenate. Treatment with the Polymyxin-B and Dantrolene combination significantly ameliorated cardiac hypertrophy, biochemical parameters, ECG parameters, and heart histopathology. Further, significant attenuation in CaMKII levels was observed. The effect of the combination was more than per se treatment. Results of the current study showed that the combination of Polymyxin-B and Dantrolene prevented the development of isoproterenol-induced hypertrophic cardiomyopathy in rats via attenuation of the CaMKII., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Purpose: A case of loperamide-induced recurrent torsades de pointes is reported to raise awareness of an increasingly common phenomenon that could be encountered by medical providers during the current opioid epidemic., Summary: A 40 year-old-man with a prior history of opioid abuse who presented to the emergency department after taking up to 100 tablets of loperamide 2 mg daily for 5 years to blunt opioid withdrawal symptoms and was subsequently admitted to the intensive care unit for altered mental status and hyperthermia. The patient had prolonged QTc and 2 episodes of torsades de pointes (TdP) that resulted in cardiac arrest with return of spontaneous circulation. He was managed with isoproterenol, overdrive pacing, and methylnatrexone with no other events of TdP or cardiac arrest., Conclusion: A 40-year-old male who developed torsades de pointes from loperamide overdose effectively treated with overdrive pacing, isoproterenol, and methylnatrexone.

Myocardial hypertrophy (MH) is an independent risk factor for cardiovascular disease, which in turn lead to arrhythmia or heart failure. Therefore, attention must be paid to formulation of therapeutic strategies for MH. Puerarin is a key bioactive ingredient isolated from Pueraria genera of plants that is beneficial for the treatment of MH. However, its molecular mechanism of action has not been fully determined. In the present study, 40 µM puerarin was demonstrated to be a safe dose for human AC16 cells using Cell Counting Kit‑8 assay. The protective effects of puerarin against MH were demonstrated in AC16 cells stimulated with isoproterenol (ISO). These effects were characterized by a significant decrease in surface area of cells (assessed using fluorescence staining) and mRNA and protein expression levels of MH‑associated biomarkers, including atrial and brain natriuretic peptide, assessed using reverse transcription‑quantitative PCR and western blotting, as well as β‑myosin heavy chain mRNA expression levels. Mechanistically, western blotting demonstrated that puerarin inhibited activation of the Wnt signaling pathway. Puerarin also significantly decreased phosphorylation of p65; this was mediated via crosstalk between the Wnt and NF‑κB signaling pathways. An inhibitor (Dickkopf‑1) and activator (IM‑12) of the Wnt signaling pathway were used to demonstrate that puerarin‑mediated effects alleviated ISO‑induced MH via the Wnt signaling pathway. The results of the present study demonstrated that puerarin pre‑treatment may be a potential therapeutic strategy for preventing ISO‑induced MH and managing MH in the future.

Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 μM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD 90 ; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD 90 present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 μM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout (Mog1 -/- ) mice. Mog1 -/- mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1 -/- mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1 -/- mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1 -/- mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix (Mmp2), gap junction (Gja1), and mitochondrial components that were dysregulated in Mog1 -/- mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1 -/- mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1 -/- mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1 -/- mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1 -/- mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1 -/- mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Coumarins and their derivatives are becoming a potential source for new drug discovery due to their vast array of biological activities. The present study was designed to investigate the cardioprotective effects of a newly synthesised coumarin, symbolised as 5,6-PhSHC, against cardiac remodelling process in isoproterenol (ISO) induced myocardial infarction (MI) in male Wistar rats by evaluating haematological, biochemical and cardiac biomarkers. Rats were pre/co-treated with 5,6-PhSHC or clopidogrel (150 μg/kg body weight) daily for a period of 7 days and then MI was induced by injecting ISO (85 mg/kg body weight), at an interval of 24 hours for 2 consecutive days, on the sixth and seventh days. The in vivo exploration indicated that the injection of 5,6-PhSHC improved the electrocardiographic (ECG) pattern and prevented severe heart damage by reducing leakage of the cardiac injury markers, such as troponin-T (cTn-T), lactate dehydrogenase (LDH), and creatine kinase-MB. The cellular architecture of cardiac sections, altered in the myocardium of infracted rats, was reversed by 5,6-PhSHC treatment. Results showed that injection of 5,6-PhSHC elicited significant cardioprotective effects by prevention of myocardium cell necrosis and inflammatory cells infiltration, along with marked decrease in plasma levels of fibrinogen. In addition, the total cholesterol, triglyceride, LDL-c, and HDL profiles underwent remarkable beneficial changes. It was also interesting to note that 5,6-PhSHC enhanced the antioxidative defence mechanisms by increasing myocardial glutathione (GSH) level, superoxide dismutase (SOD), and catalase (CAT) activities, together with reducing the levels of thiobarbituric-acid-reactive substances (TBARS), when compared with ISO-induced rats. Taken together, these findings suggested a beneficial role for 5,6-PhSHC against ISO-induced MI in rats. Furthermore, in silico analysis showed that 5,6-PhSHC possess high computational affinities (E-value >-9.0 kcal/mol) against cyclooxygenase-2 (PDB-ID: 1CX2), vitamin K epoxide reductase (PDB-ID: 3KP9), glycoprotein-IIb/IIIa (PDB-ID: 2VDM) and catalase (PDB-ID: 1DGF). Therefore, the present study provided promising data that the newly synthesised coumarin can be useful in the design and synthesis of novel drug against myocardial infarction., (© 2022 John Wiley & Sons Australia, Ltd.)

Combination drug therapy has become an effective strategy for chronic metabolic disease, especially cardiovascular disease. In the present study, possible drug combinations were screened and the mechanism of the combinations against cardiac hypertrophy was examined within 1,8-cineole, β-caryophyllene, linalool, and β-pinene.H9c2 cells were treatment with 1,8-cineole, β-caryophyllene, linalool, and β-pinene individually or in combination for 24 h after isoprenaline stimulation. Cell viability was detected by the MTT assay. Subsequently, bioinformatic analysis and network pharmacology were used to reveal the multi-targeted synergistic therapeutic effect of the combination treatment compounds on cardiac hypertrophy. Ultimately, western blot and elisa was performed to analyses the protein expression in vivo. MTT results found that 1,8-cineole and β-caryophyllene synergistically increased cell viability with CalcuSyn software analyses. Specifically, bioinformatic and network pharmacology analysis showed PTGS2, TNF, IL-6, AKT1, NOS2, and CAT were identified as the key targets. P13K-AKT signaling pathway was involved in the reversal of cardiac hypertrophy by the combination of 1,8-cineole and β-caryophyllene. The in vitro results indicated that the combination synergistically treated the isoprenaline-induced mice against structural and functional myocardial damage via the P13K-AKT signaling pathway. Collectively, the combined application of 1,8-cineole and β-caryophyllene synergistically reverses cardiac hypertrophy in isoprenaline-induced H9c2 cells and mice., (Copyright © 2022. Published by Elsevier Inc.)

The role of oxidative injury and inflammatory response in cardiovascular diseases and heart failure has been well-acknowledged. This study evaluated the protective effect of umbelliferone (UMB), a coumarin with promising radical scavenging and anti-inflammatory activities, on myocardial injury induced by isoproterenol (ISO) in rats. Rats received 50 mg/kg UMB orally for 14 days and 85 mg/kg ISO twice at an interval of 24 h. Administration of ISO elevated serum troponin I, creatine kinase-MB and lactate dehydrogenase, and caused histopathological alterations, including degeneration, fatty vacuolation, myolysis, and atrophy of myocardial fibers. Malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β were increased, whereas reduced glutathione (GSH), superoxide dismutase (SOD), and catalase were decreased in ISO-administered rats. UMB effectively ameliorated myocardial injury, alleviated cardiac function markers, MDA, NO, NF-κB p65, and the inflammatory mediators, and enhanced cellular antioxidants. Bax, caspase-3, and 8-OHdG were decreased, and Bcl-2 was increased in ISO-administered rats treated with UMB. In addition, UMB upregulated nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 in the heart of ISO-administered rats. In conclusion, UMB can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cucumis sativus L., widely cultivated as an edible vegetable. Its seeds are well reputed for cardiovascular preventive properties. However, the mechanisms underlying for cardiovascular protection of C. sativus are still unidentified. Therefore, this study utilized a metabolomics approach to investigate putative mechanisms of C. sativus seeds in myocardial infarction (MI) and in vitro models of vasoconstriction, atrium, and invasive blood pressure measurement. Results showed that Cu.EtOH extract showed a vasorelaxant response with potent hypotensive effect in normotensive rats and L-NAME induced hypertension. Cu.EtOH caused a negative inotropic and positive chronotropic effect on the atrium. Cu.EtOH protected the animals from ISO-induced myocardial infarction (MI) interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, and biochemical assays. The metabolomics data suggested that Cu.EtOH mainly affected amino acid metabolism, BCAA degradation, ketone bodies degradation, and oxidative stress. Our study showed that Cu.EtOH suppressed inflammation with a strong anti-myocardial infarction impact. Additionally, our findings indicated Cu.EtOH reverted the amino acid metabolism, BCAA, and ketone bodies degradation. The findings show the antihypertensive mechanism of Cu.EtOH may include the modulation of endothelium-derived relaxing factor (EDRF) produced from nitric oxide (NO) and is connected with vascular endothelial function. C. sativus seeds, in particular, played a pivotal role in the treatment of myocardial and vascular disorders by enhancing the EDRF mechanism, energy generation, and antioxidant capacity. In summary, our findings showed the mechanistic insights on the therapeutic potential of C. sativus seeds for cardiovascular disorders., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A common cause of mortality around the world is ischemic myocardial injury. The study was conducted to examine the ability of amniotic membrane mesenchymal stem cells (AMSCs) for protection against isoproterenol (ISO)-induced myocardial injury and attempted to show the possible mechanisms by which AMSCs that can be linked to inhibition of inflammation by targeting inflammatory MAPK/NF-κB pathway. Model was established by subcutaneous injection of 170 mg/kg/day of ISO for four consecutive days. Flow cytometry and echocardiography were carried out to evaluate characterization of hAMSCs and cardiac function, respectively. The expression of inflammatory cytokines was determined using ELISA assay. The activities of NF-κB and phosphorylated p38 MAPK were measured using immunohistochemical assessments. The results showed that ISO administration was resulted in cardiac dysfunction, increased levels of inflammatory cytokines that reversed by intramyocardially administration of AMSCs (P < 0. 05). Cardioprotective effects of AMSCs were associated with a significant decreased expression of NF-κB and reduced levels of phosphorylated p38 MAPK (P < 0. 05). In conclusion, our finding showed that intramyocardially administration of AMSCs could contribute to improvement of heart function and inhibition of inflammation in the site of injury by targeting inflammatory MAPK/NF-κB pathway., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Acute β-adrenergic stimulation contributes to heart failure. Here, we investigated the role of p53 in isoproterenol (ISO)-mediated metabolic and oxidative stress effects on cardiomyocytes and explored the direct protective effects offered by the antioxidant nutraceutical curcumin. Differentiated H9C2 rat cardiomyocytes treated with ISO were assayed for glucose uptake, lactate release, and mitochondrial reactive oxygen species (ROS) generation. Survival was assessed by sulforhodamine B assays. Cardiomyocytes showed significantly decreased glucose uptake and lactate release, as well as increased cellular toxicity by ISO treatment. This was accompanied by marked dose-dependent increases of mitochondria-derived ROS. Scavenging with N-acetyl-L-cysteine (NAC) effectively lowered ROS levels, which completely recovered glycolytic metabolism and survival suppressed by ISO. Mechanistically, ISO reduced extracellular-signal-regulated kinase (ERK) activation, whereas it upregulated p53 expression in an ROS-dependent manner. Silencing of p53 with siRNA blocked the ability of ISO to stimulate mitochondrial ROS and suppress glucose uptake, and partially recovered cell survival. Finally, curcumin completely reversed the metabolic and ROS-stimulating effects of ISO. Furthermore, curcumin improved survival of cardiomyocytes exposed to ISO. Thus, ISO suppresses cardiomyocyte glycolytic metabolism and survival by stimulating mitochondrial ROS in a p53-dependent manner. Furthermore, curcumin can efficiently rescue cardiomyocytes from these adverse effects.

We studied the effect of Angipur on the process of experimental thrombosis induced by damage to the carotid artery wall by surface application of 50% ferric chloride (III) solution in rats without comorbidities and with isoproterenol-induced myocardial infarction. In animals without comorbidities, Angipur administered intravenously was 1.2 times less effective, in terms of ED 50 , than the well-known inhibitor of GPIIb/IIIa platelet receptors tirofiban. However, under conditions of non-coronary myocardial infarction, Angipur significantly prolonged the time of thrombus formation and exhibited 1.4-fold higher activity than the reference drug tirofiban., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Cardiovascular disorders are the leading cause of death globally. Rosuvastatin is a member of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) with many pleiotropic properties. This study investigated cardioprotective effects of rosuvastatin in isoprenaline-induced myocardial injury. Male rats were given rosuvastatin (1, 5, or 10 mg/kg, oral) daily for 1 week and on seventh and eighth day isoprenaline (150 mg/kg, subcutaneous) was given to induce cardiac injury. On ninth day, rats were euthanized and different samples were harvested for analysis. Isoprenaline administration resulted in increased cardiac mass, increased cardiac injury marker levels (cTnI, CK-MB, ALT, and AST), increased lipid/protein oxidation, and increased cardiac nitrite levels. It also decreased superoxide dismutase, CAT, GST, and glutathione reductase activities, and total antioxidant activity. Isoprenaline also increased TNF-α and IL-6 levels. Decreased mRNA expression of Nrf2 and Bcl-2 along with increased mRNA expression of Bax, eNOS and iNOS genes was observed in isoprenaline treated animals. Histopathological evaluations of rosuvastatin pre-treated groups showed reduction of myocardial necrosis. Pretreatment with rosuvastatin (5 and 10 mg/kg) reduced many of these pathological changes. The current study showed that rosuvastatin significantly reduces myocardial injury induced by isoprenaline.

Schisandrin A (Sch A) has a protective effect on cardiomyocytes. Circulating miR‑155 levels are related to chronic heart failure (CHF). The present study aimed to clarify the role and the molecular mechanism of Sch A in CHF. C57BL/6JGpt mice were used for an isoproterenol (ISO)‑induced CHF model to collect heart samples. Echocardiography was employed to detect heartbeat indicators. The degree of myocardial hypertrophy was evaluated based on the measurement of heart weight (HW), body weight (BW) and tibia length (TL) and the observation using hematoxylin‑eosin staining. Sprague‑Dawley rats were purchased for the separation of neonatal rat ventricular myocytes (NRVMs), which were treated with ISO for 24 h. Transfection regulated the level of miR‑155. The viability of NRVMs was detected via MTT assay. The mRNA and protein levels were measured via reverse transcription‑quantitative PCR and western blotting and immunofluorescence was used to detect the content of α‑smooth muscle actin (α‑SMA). Treatment with ISO resulted in rising left ventricular posterior wall thickness, intra‑ventricular septum diastole, left ventricular end diastolic diameter, left ventricular end systolic diameter, HW/BW, HW/TL and falling ejection fraction and fractional shortening, the trend of which could be reversed by Sch A. Sch A ameliorated myocardial hypertrophy in CHF mice. In addition, Sch A inhibited ISO‑induced upregulated expressions of atrial natriuretic peptide, B‑type natriuretic peptide, B‑myosin heavy chain and miR‑155 in myocardial tissue. Based on the results in vitro , Sch A had no significant effect on the viability of NRVMs when its concentration was <24  µ mol/l. Sch A inhibited the levels of miR‑155, α‑SMA and the phosphorylation levels of AKT and cyclic AMP response‑element binding protein (CREB) in ISO‑induced NRVMs, which was reversed by the upregulation of miR‑155. Schisandrin A mediated the AKT/CREB signaling pathway to prevent CHF by regulating the expression of miR‑155, which may shed light on a possible therapeutic target for CHF.

Background: Takotsubo syndrome (TTS) is a stress-induced disorder affecting mostly postmenopausal women. The aim of the study was to evaluate isoprenaline (ISO) dependent female rat model and histopathological characteristics in TTS., Methods: Forty-nine Sprague Dawley female rats, 12 weeks old, were injected intraperitoneally with a single dose of ISO at doses 50 (n = 8), 75 (n = 6), 100 (n = 3), 150 (n = 27) and 200 (n = 5) mg/kg body weight (bw). The control group (n = 6) was injected with physiological saline. The echocardiographic examination to assess wall motion abnormalities took place 24, 48, 72 h, and 7 days post-ISO. Histopathological analysis was performed on the basis of hematoxylin-eosin staining., Results: The total mortality rate was 3/49 (6.12%). The optimum dose of ISO to induce TTS was 150 mg/kg bw and 21/27 (77.77%) rats showed apical ballooning. Histopathological analysis revealed focal necrosis/apoptosis of cardiomyocytes with inflammatory and fibroblast-like cell infiltration. Foci were the most numerous in the central muscle layer with apical-basal gradient 24, 48, 72 h post-ISO (p < 0.05). Significant differences were noted 48 h post-ISO in the central layer in apical vs basal segments (p = 0.0032), in the endocardial layer in apical vs basal segments (0.00024) and in mid-cavital vs. basal segments (p = 0.0483). The number of foci in endocardium of apical region differ 48 h post-ISO in rats with a dose of 150 vs. 200 mg/kg bw (p = 0.0084)., Conclusions: The ISO female rat model of TTS is associated with higher optimum dose and lower mortality in comparison with the male TTS model. TTS presents as a singles cardiomyocyte disorder, foci concerned mainly central muscle layer with apical-basal gradient.

Oxidative tissue injury and inflammatory responses play major roles in cardiovascular diseases and heart failure. Visnagin (VIS) is a natural bioactive component of Ammi visnaga, with promising radical scavenging and anti-inflammatory activities. This study explored the protective effect of VIS against isoproterenol (ISO)-induced acute myocardial injury and oxidative stress in rats. VIS was supplemented for 14 days, and the rats received ISO (100 mg/kg) twice at an interval of 24 h. ISO-induced myocardial injury was characterized by elevated serum CK-MB, LDH, and troponin-I associated with increased heart weight and several histopathological changes. ISO increased reactive oxygen species (ROS), malondialdehyde (MDA), NF-κB p65, TNF-α, IL-6, and decreased glutathione and antioxidant enzymes in rats' hearts. VIS prevented myocardial injury and ameliorated the cardiac function markers, ROS, MDA, NF-κB p65, and pro-inflammatory cytokines in ISO-intoxicated rats. In addition, VIS decreased Bax mRNA and caspases, and upregulated Nrf2, HO-1, Bcl-2, and PPARγ. Molecular docking simulations revealed the binding method of VIS to NF-κB, Keap1, and PPARγ. In conclusion, VIS protects against ISO-induced acute myocardial injury by attenuating oxidative tissue injury and reducing key inflammatory and apoptosis markers. In vivo and in silico results showed that activation of Nrf2/HO-1 signaling and PPARγ mediates the cardioprotective effect of VIS., (© 2021 Wiley Periodicals LLC.)

Aims: Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline-induced takotsubo-like phenotype in rats., Methods and Results: A total number of 186 Sprague-Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high-resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS-like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0., Conclusions: Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenaline-induced apical akinesia in the TTS-like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

We recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early β-adrenergic stimulation. Here we characterized macrophages (Mφ) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and Mφ-depletion experiments evidenced a transient increase in Mφ number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized Mφ-enriched CD45 + cells from ECH hearts as CX3CL1- and TNFα-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1 -/- knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH Mφ proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNFα. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting Mφ and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF., (© 2021. The Author(s).)

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.

This study is carried out to assess the cardiopreventive effect of (E)-N'-(1-(7-methoxy-2-oxo-2H-chromen-3-yl) ethylidene)-4-methylbenzenesulfonohydrazide or SHC, a novel synthesized coumarin, against myocardial infarction induced by isoproterenol (ISO). The SHC compound was identified and characterized by spectral methods (infrared, 1 H NMR [nuclear magnetic resonance], 13 C NMR, Nuclear Overhauser Effect Spectroscopy, and high-resolution mass spectroscopy). Male Wistar rats were divided into four groups: Control, ISO (rats were injected subcutaneously by 85 mg/kg body weight [BW] of isoproterenol at Days 6 and 7 of the experience), ISO + SHC (150 µg/kg BW, orally for 7 days) and ISO + acenocoumarol (150 µg/kg BW, orally for 7 days). Results showed that ISO induced a remarkable alteration of electrocardiogram (ECG) pattern and increases of plasma cardiac troponin T, creatine kinase-MB, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, lactate dehydrogenase, aspartate transaminase, and malondialdehyde. In addition, ISO reduced the high-density lipoprotein-cholesterol content and the activities of superoxide dismutase and glutathione peroxidase, with the induction of myocardial necrosis. However, SHC administration revealed a significant decrease in cardiac dysfunction markers, restored normal ECG pattern, as well as improving lipids parameters. Moreover, SHC treatment remarkably alleviated the cardiac oxidative stress and the myocardial remodeling process. Overall, the SHC offers good protection from acute myocardial infarction through the antioxidant capacity., (© 2021 Wiley Periodicals LLC.)

Background: Although heart failure (HF) with preserved ejection fraction (HFpEF) is more common in postmenopausal women than in men, the effect of sex hormones on cardiac diastolic function remains unclear. We examined the effect of gonadectomy with or without the angiotensin receptor blocker olmesartan (Olm) in an isoproterenol (ISO) -induced mouse model of left ventricular hypertrophy (LVH) and cardiac diastolic dysfunction., Methods: ISO or ISO with Olm were administered for 28 days in sham-operated male and female, castrated (CAS), and ovariectomized (OVX) mice. LV ejection fraction (EF) and E/A ratio were analyzed by echocardiography, and the LV and lung weight corrected by tibial length were used as indices of LVH and lung congestion, respectively., Results: On echocardiography, systolic function did not differ between the four groups. LV/tibial length (TL) and Lung/TL significantly increased in all groups. The LV/TL ratio was lower in castrated-ISO vs. Male-Sham-ISO but did not differ between Female-Sham-ISO and OVX-ISO. However, the Lung/TL ratio of OVX-ISO was greater than that of Female-Sham-ISO. Olm prevented LV hypertrophy in all groups. The decrease in E/A and increase in lung weight were improved by Olm in Male-Sham and OVX-ISO but not in the other groups., Conclusion: These sex differences suggest that sex hormones play a pivotal role in modulating cardiac hypertrophy and diastolic dysfunction induced by chronic β-adrenoceptor stimulation, and thus affect the therapeutic potential of angiotensin receptor blockade.

Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.

A scientific approach is presented describing the fabrication of nanoprobe (GloTrack) that can act as cardiac precursor label to segregate cells from cardiac/non cardiac origins and traced by magnetic resonance imaging (MRI). Signal regulatory protein alpha (SIRPA) and kinase domain receptor (KDR) recognizing antibodies, form a layer on super paramagnetic iron oxide nanoparticle - poly-ethylene glycol (SPION-PEG) complex, and bind to protein expressed on the surface of cardiac muscle cells. Physical attributes size, distribution, labelling efficiency, echocardiogram (ECG) changes and bio-distribution by MRI were analysed. The results indicate that GloTrack has an average size of 471 nm, exhibits negative potential and promotes labelling efficiency. The bio-distribution of GloTrack in in vivo experiments was traceable in 7T MRI showing high accumulation of GloTrack in cardiac muscles as compared to the liver and spleen. ECG data revealed that GloTrack segregated cardiac precursors has the potential benefit in treating heart failure, thereby paving way in the development of minimal cell manipulation with targeted cell delivery approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Natural products still serves as a hope for some illnesses which modern medicine fails to cure. Many people, either knowing their effects or not, are using these herbal products. Treatment of chronic heart failure (CHF) is yet a complicated clinical challenge and there is need to improve or make new therapeutic targets. Finding new agents for CHF is an important subject in cardiovascular drug research. In this study, we evaluated the effects of ten herbals on treatment of CHF on isoproterenol-induced model., Methods and Results: Ninety-six male Wistar rats (16 weeks old) were used in 12 groups. Transthoracic echocardiography was performed on the rats for confirmation of CHF model by decreasing ejection fraction. After 4 weeks' treatment, hearts were removed and blood samples were collected in tubes to measure plasma levels of laboratory findings. Our results showed that the mean of ejection fraction in model rats was 51.82 ± 3.49 percent and all of our used natural products could significantly increase the ejection fraction (P < 0.01). The most effective herbals in improving the ejection fraction were Allium sativum (30.69 %), Peganum harmala (26.08 %) and Apium graveolens (24.09 %). The best results in decreasing NT-ProBNP, was obtained from Allium sativum, Peganum harmala and Berberis vulgaris respectively. Our results showed that none of natural products had toxic effect on renal and liver tissues., Conclusion: Our results showed that Allium sativum, Peganum harmala and Berberis vulgaris could significantly improve cardiac function by improvement of left ventricular remodeling, lowering hs-CRP and NT-ProBNP and echocardiographic indexes without liver or renal side effects., (Copyright © 2020. Published by Elsevier Masson SAS.)

As a traditional plant medicine in tropical areas, Swietenia macrophylla seeds are usually applied for some chronic diseases, including hypertension, diabetes, and so on. Few studies have been carried out to identify the effective elements in seed extract and their indications. In this study, we first investigated the functions of the swietenine, an extract from S. macrophylla seeds, using a model of myocardial hypertrophy induced by isoprenaline (ISO). At cellular level, H9c2 cell hypertrophy was also established through the treatment with ISO. The cardiac pathological remodeling was evaluated by echocardiography and histological analysis. Western blot and RT-qPCR were used to detect the expression of possible hypertrophy-promoting genes. Here, our results indicated that swietenine remarkably attenuated ISO-induced myocardial hypertrophy in vivo and in vitro. Moreover, Akt phosphorylation, ANP and BNP mRNA expression were efficiently decreased. Based on these findings, we concluded that swietenine might be a promising anti-hypertrophic agent against cardiac hypertrophy., (© 2020 Wiley Periodicals LLC.)

Boron is an essential trace element in cellular metabolism; however, the molecular mechanism of boron in the heart is unclear. In this study, we examined the effect of sodium tetraborate (as boron source) as a possible protective agent or competitive inhibitor of cardiac hypertrophy in an in vitro murine model. We evaluated different previously reported sodium tetraborate concentrations and it was found that 13 μM improves viability without affecting the cellular structure. We demonstrated that cardiomyocytes pretreated with sodium tetraborate prevents cellular damage induced by isoproterenol (cardioprotective effect) by increasing proliferation rate and inhibiting apoptosis. In addition, the reduction of the expression of the α1AR and β1AR adrenergic receptors as well as Erk1/2 was notable. Consequently, the expression of the early response genes c-myc, c-fos and c-jun was delayed. Also, the expression of GATA-4, NFAT, NKx2.5 and myogenin transcription factors involved in sarcomere synthesis declined. In contrast, cardiomyocytes, when treated simultaneously with sodium tetraborate and isoproterenol, did not increase their size (cytoplasmic gain), but an increase in apoptosis levels was observed; therefore, the proliferation rate was reduced. Although the mRNA levels of α1AR and β1AR as well as Erk1/2 and Akt1 were low at 24 h, their expression increased to 48 h. Notably, the mRNA of expression levels of c-myc, c-fos and c-jun were lower than those determined in the control, while the transcription factors GATA-4, MEF2c, Nkx2.5, NFAT and CDk9 were determined in most cells. These results suggest that pretreatment with sodium tetraborate in cardiomyocytes inhibits the hypertrophic effect. However, sodium tetraborate attenuates isoproterenol induced hypertrophy damage in cardiomyocytes when these two compounds are added simultaneously., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Diabetes is a leading cause of chronic kidney disease, and the high prevalence of sympathetic nervous system (SNS) hyperactivity in diabetic patients makes them further susceptible to SNS-mediated oxidative stress and accelerated kidney damage. Here, we investigated if canagliflozin can reverse isoprenaline (ISO)-induced renal oxidative damage in rats, a model that mimics SNS overstimulation-induced organ injuries in humans. We found that ISO administration elevates renal oxidative stress markers including malondialdehyde (MDA), advanced protein oxidation product (APOP), myeloperoxidase (MPO) and nitric oxide (NO), while depleting levels of endogenous antioxidants such as catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH). Strikingly, canagliflozin treatment of ISO-treated rats not only prevents elevation of oxidative stress markers but also rescues levels of depleted antioxidants. Our results also show that canagliflozin stimulates antioxidant/anti-inflammatory signaling pathways involving AMP-activated protein kinase (AMPK), Akt and eNOS, and inhibits iNOS and NADPH oxidase isoform 4 (NOX4), all of which are associated with oxidative stress and inflammation. Further, canagliflozin prevents ISO-induced apoptosis of kidney cells by inhibiting Bax protein upregulation and caspase-3 activation. Histological examination of kidney sections reveal that canagliflozin attenuates ISO-mediated increases in inflammatory cell infiltration, collagen deposition and fibrosis. Finally, consistent with these findings, canagliflozin treatment improves kidney function in ISO-treated rats, suggesting that the antioxidant effects may be clinically translatable.

To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca 2+ /calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the Ca V 1.2 channel and amounts of CaMKII bound with HDAC4 and Ca V 1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with Ca V 1.2 could be potential targets to achieve effective regression of cardiac hypertrophy., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background Cardiac remodeling predisposes individuals to heart failure if the burden is not solved, and heart failure is a growing cause of morbidity and mortality worldwide. The cardiac extracellular matrix not only provides structural support, but also is a core aspect of the myocardial response to various biomechanical stresses and heart failure. MFAP4 (microfibrillar-associated protein 4) is an integrin ligand located in the extracellular matrix, whose biological functions in the heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods and Results MFAP4-deficient (MFAP4 -/- ) and wild-type mice were subjected to aortic banding surgery and isoproterenol to establish models of cardiac remodeling. We also evaluated the functional effects of MFAP4 on cardiac hypertrophy, fibrosis, and cardiac electrical remodeling. The expression of MFAP4 was increased in the animal cardiac remodeling models induced by pressure overload and isoproterenol. After challenge of 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol, MFAP4 -/- mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias than wild-type mice. However, there was no significant effect on cardiomyocyte hypertrophy. In addition, there was no significant difference in cardiac fibrosis severity, hypertrophy, or ventricular arrhythmia incidence between wild-type-sham and knockout-sham mice. Conclusions These findings are the first to demonstrate that MFAP4 deficiency inhibits cardiac fibrosis and ventricular arrhythmias after challenge with 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol but does not significantly affect the hypertrophy response. In addition, MFAP4 deficiency had no significant effect on cardiac fibrosis, hypertrophy, or ventricular arrhythmia in the sham group in this study.

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Scope: [6]-Gingerol is one of the primary pungent constituents of ginger. While [6]-gingerol has many pharmacological effects, its benefits for myocardial fibrosis, including its exact role and underlying mechanisms, remain largely unexplored. The present study is designed to characterize the cardio-protective effects of [6]-gingerol in myocardial fibrosis mice and possible underlying mechanisms., Methods and Results: Mice are subcutaneously injected with isoproterenol (ISO, 10 mg kg -1 ) and gavaged with [6]-gingerol (10, 20 mg kg -1 day -1 ) for 14 days. Pathological alterations, fibrosis, oxidative stress, inflammation response, and apoptosis are examined. In ISO-induced myocardial fibrosis, [6]-gingerol treatment decreases the J-point, heart rate, cardiac weight index, left ventricle weight index, creatine kinase (CK), and lactate dehydrogenase serum levels, calcium concentration, reactive oxygen species, malondialdehyde, and glutathione disulfide (GSSG), and increases levels of superoxide dismutase, catalase, glutathione, and GSH/GSSG. Further, [6]-gingerol improved ISO-induced morphological pathologies, inhibited inflammation and apoptosis, and suppressed the toll-like receptor-4 (TLR4)/mitogen-activated protein kinases (MAPKs)/nuclear factor κB (NF-κB) signaling pathways., Conclusion: The protective effect of [6]-gingerol in mice with ISO-induced myocardial fibrosis may be related to the inhibition of oxidative stress, inflammation, and apoptosis, potentially through the TLR4/MAPKs/NF-κB signaling pathway., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)