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Ongoing inflammation in the heart is positively correlated with adverse remodeling, characterized by elevated levels of cytokines that stimulate activation of cardiac fibroblasts. It was found that CaMKIIδ response to Ang II or TAC triggers the accumulation of ROS in cardiomyocytes, which subsequently stimulates NF-κB/NLRP3 and leads to an increase in IL-6, IL-1β, and IL-18. This is an important causative factor in the occurrence of adverse remodeling in heart failure. Sweroside is a biologically active natural iridoids extracted from Lonicerae Japonicae Flos. It shows potent anti-inflammatory and antioxidant activity in various cardiovascular diseases. In this study, we found that sweroside inhibited ROS-mediated NF-κB/NLRP3 in Ang II-treated cardiomyocytes by directly binding to CaMKIIδ. Knockdown of CaMKⅡδ abrogated the effect of sweroside regulation on NF-κB/NLRP3 in cardiomyocytes. AAV-CaMKⅡδ induced high expression of CaMKⅡδ in the myocardium of TAC/Ang II-mice, and the inhibitory effect of sweroside on TAC/Ang Ⅱ-induced elevation of NF-κB/NLRP3 was impeded. Sweroside showed significant inhibitory effects on CaMKIIδ/NF-κB/NLRP3 in cardiomyocytes from TAC/Ang Ⅱ-induced mice. This would be able to mitigate the adverse events of myocardial remodeling and contractile dysfunction at 8 weeks after the onset of the inflammatory response. Taken together, our findings have revealed the direct protein targets and molecular mechanisms by which sweroside improves heart failure, thereby supporting the further development of sweroside as a therapeutic agent for heart failure., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Heart failure is a process characterized by significant disturbance of protein turnover. To elucidate the alterations in cardiac protein expression during the various phases of heart failure and to understand the nature of the processes involved, we analysed the proteome in an established heart failure model at different time points to monitor thousands of different proteins simultaneously. Here, heart failure was induced by transverse aortic constriction (TAC) in KM mice. At 2, 4 and 12 weeks after operation, protein expression profiles were determined in sham-operated (controls) and TAC mice, using label-free quantitative proteomics, leading to identification and quantification of almost 4000 proteins. The results of the KEGG pathway enrichment analysis and GO function annotation revealed critical pathways associated with the transition from cardiac hypertrophy to heart failure, such as energy pathways and matrix reorganization. Our study suggests that in the pathophysiology of heart failure, alterations of protein groups related to cardiac energy substrate metabolism and cytoskeleton remodelling could play the more dominant roles for the signalling that eventually results in contractile dysfunction and heart failure., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Myocardial fibrosis is an important pathological feature of pressure overload cardiac remodeling. Si-Miao-Yong-An decoction (SMYAD), a traditional Chinese formula, is now clinically used in the treatment of cardiovascular diseases in China. However, its mechanisms in the prevention of heart failure are not fully revealed., Purpose: To determine whether treatment with SMYAD for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a mice model of heart failure., Methods: Mice were subjected to transverse aorta constriction to generate pressure overload induced cardiac remodeling and then were administered SMYAD (14.85 g/kg/day) or captopril (16.5 mg/kg/day) intragastrically for 4 weeks after surgery. Echocardiography and immunohistochemical examination were used to evaluate the effects of SMYAD. The mRNA of collagen metabolism biomarkers were detected. Protein expression of TGF-β1/Smad and TGF-β1/TAK1/p38 pathway were assessed by Western blot., Results: SMYAD significantly improved cardiac function, increased left ventricle ejection fraction, and decreased fibrosis area and αSMA expression. Moreover, SMYAD reduced proteins expression related to collagen metabolism, including Col1, Col3, TIMP2 and CTGF. The increased levels of TGF-β1, Smad2, and Smad3 phosphorylation were attenuated in SMYAD group. In addition, SMYAD reduced the levels of TGF-β1, p-TAK1 and p-p38 compared with TAC group., Conclusions: SMYAD improved cardiac fibrosis and heart failure by inhibition of TGF-β1/Smad and TGF-β1/TAK1/p38 pathway. SMYAD protected against cardiac fibrosis and maintained collagen metabolism balance by regulating MMP-TIMP expression. Taken together, these results indicate that SMYAD might be a promising therapeutic agent against cardiac fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Si-Miao-Yong-An decoction (SMYAD), a Chinese herbal formula, has been used in treating ischemic cardiovascular diseases. However, the cardioprotective mechanism of SMYAD treating heart failure (HF) remains unclear. Herein we investigated the effect of SMYAD on isoprenaline (ISO)-induced HF in C57BL/6 mice. Cardiac function and pathological changes in myocardial tissue were evaluated as well as A-type natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression. The underlying mechanism of SMYAD was deciphered using UHPLC MS/MS coupled with bioinformatics and was verified. SMYAD treatment significantly ameliorated cardiac function, reduced collagen deposition and cardiomyocyte apoptosis, reversed cardiac hypertrophy and down-regulated the expression levels of ANP and BNP mRNA compared with those in HF mice. Decipherment analyses based on 138 ingredients prompted that anti-oxidation was the key mechanism of SMYAD treating HF. In vitro and in vivo, SMYAD showed antioxidant activity, significantly up-regulated superoxide dismutase (SOD)-1 and SOD-2 mRNA expression levels and reduced NADP/NADPH ratio. Moreover, the increased expression levels of NADPH oxidase 2 (NOX2), p47 phox and Rac family small GTPase 1 (Rac1) were obviously ameliorated after SMYAD treatment. Together, this study reveals that SMYAD can apparently improve heart function of ISO-induced HF mice by inhibiting the myocardial oxidative stress through restoring the equilibrium of SOD and NOX2., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Qishen granules (QSG) have beneficial therapeutic effects for heart failure, but the effects of decomposed recipes, including Wenyang Yiqi Huoxue (WYH) and Qingre Jiedu (QJ), are not clear. In this study, the efficacy of WYH and QJ on heart failure is evaluated by using transverse aortic constriction (TAC) induced mice and the significantly changed genes in heart tissues were screened with a DNA array. Furthermore, a new quantitative pathway analysis tool is developed to evaluate the differences of pathways in different groups and to identify the pharmacological contributions of the decomposed recipes. Finally, the related genes in the significantly changed pathways are verified by a real-time polymerase chain reaction and a Western blot. Our data show that both QJ and WYH improve the left ventricular ejection fraction, which explain their contributions to protect against heart failure. In the energy metabolism, QJ achieves the therapeutic effects of QSG through nicotinamide nucleotide transhydrogenase (Nnt)-mediated mechanisms. In ventricular remodeling and inflammation reactions, QJ and WYH undertake the therapeutic effects through 5'-nucleotidase ecto (Nt5e)-mediated mechanisms. Together, QJ and WYH constitute the therapeutic effects of QSG and play important roles in myocardial energy metabolism and inflammation, which can exert therapeutic effects for heart failure.

Background: Chinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation., Methods: DanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation., Results: A novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand-receptor interaction, calcium-signaling pathway, and aminoacyl-tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP., Conclusions: The combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.

Background: Despite major advances in the treatment of heart failure (HF), it remains the major cause of mortality and morbidity worldwide. Experimental models of HF typically utilize acute myocardial infarction. However, the majority of clinical HFs occur gradually by a chronic progressive mechanism. Thus, more relevant models are required to aid identification, quantification, and characterization of HF, and its underlying mechanisms., Methods and Findings: We developed a model of progressive chronic heart failure (CHF) in the mini-swine by placement of an ameroid constrictor on the left anterior descending coronary artery (LAD). This model demonstrated a steady decline in the cardiac function from 8 to 12 weeks, with a 50% reduction in the ejection fraction. Further, the proteomic, metabolomic and bioinformatic analyses of ischemic tissue and plasma revealed a significant alteration of the mitochondrial respiratory chain mediated by nicotinamide adenine dinucleotide (NADH), which resulted in down-regulation of malate dehydrogenase (MDH) and insufficient energy supply to support cardiac contractility and relaxation. Furthermore, significant changes in apolipoprotein A-I, low density lipoprotein (LDL), and very LDL (VLDL) in plasma indicated that lipid metabolism disorders occurred in mini-swines with myocardial ischemia via glycerolipid metabolism., Conclusions: We describe a stable and easily reproducible CHF model using an ameroid constrictor placed on the LAD. We found that the NADH-mediated tricarboxylic acid cycle and energy metabolism disorders are key pathophysiological mechanisms underlying CHF. These data will provide potential biomarkers for monitoring the therapeutic intervention of CHF.

Heart failure is the end of many kinds of cardiovascular diseases, which seriously affects human's health and brings heavy economic burden to the society. The integrated traditional Chinese medicine and Western medicine treatment for heart failure has been proved to be effective. In recent years, the understanding of the pathogenesis of heart failure from the respect of Chinese medicine has continued to be innovated, and "Du" plays an evil role in the progression of heart failure. Inflammation and oxidative stress turn into the focus of the researches on the accumulated physiological mechanisms of heart failure. In this paper, we reviewed the theoretical origins of "Du" in Chinese medicine, summarized the understanding of "Du" in heart failure by different schools of Chinese medicine, introduced the progress of research on inflammation, immunity and oxidative stress in the development of heart failure, and analyzed the mechanism of Chinese medicine in treating heart failure by regulating inflammation, immunity and anti-oxidative stress. We hope to provide some new clues and references for the further researches on the integration of Chinese medicine and Western medicine in heart failure.

Objective: The aim of this study was to determine whether Si-Miao-Yong-An decoction (SMYAD) could ameliorate pressure overload-induced heart hypertrophy and its mechanisms. Methods: C57BL/6 mice were subjected to either sham or transverse aortic constriction (TAC) surgery to induce heart hypertrophy. SMYAD (14.85 g/kg/day, ig) or captopril (16.5 mg/kg/day, ig) was administered to the mice for 4 weeks. Cardiac function was evaluated based on echocardiography. Heart hypertrophy was detected using hematoxylin and eosin or wheat germ agglutinin staining. Protein expression of CD41, CD61, and P-selectin were measured with Western blot and immunohistochemistry. The expression levels of atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain, β-thromboglobulin, and von Willebrand factor were evaluated by quantitative polymerase chain reaction. Results: Four weeks after TAC, mice developed exaggerated cardiac hypertrophy and demonstrated a strong decrease in left ventricular ejection fraction compared with sham (29.9 ± 9.3% versus 66.0 ± 9.9%; P < 0.001). Conversely, SMYAD improved cardiac dysfunction with preserved left ventricular ejection fraction (66.5 ± 17.2%; P < 0.001). Shortening fraction was increased by SMYAD, while the left ventricular internal diameter and left ventricular volume were decreased in SMYAD group. SMYAD treatment significantly attenuated cardiac hypertrophy as reflected by the inhibition of atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain mRNA expression, and by the decreasing of cardiac myocyte cross-sectional area. Furthermore, Western blot and immunohistochemistry indicated that the protein expression of platelet aggregation markers (CD41 and CD61) and platelet activation marker (P-selectin) were significantly higher in model mice compared with control. These pathological alterations in TAC-induced mice were significantly ameliorated or blocked by SMYAD administration. Conclusions: Our results suggested that SMYAD exerted its effect by inhibiting platelet aggregation and activation as revealed by CD41/CD61/P-selectin downregulation. Inhibition the activation of the platelets might contribute to the therapeutic effect of SMYAD in failing heart. [ABSTRACT FROM AUTHOR]

Background. Chinese herbal medicine (CHM) has been used in the treatment of chronic heart failure (CHF) for a long time. Treatment based on syndrome differentiation and the main characteristic of TCM is the fundamental principle of TCM practice. In this study protocol, we have designed a trial to assess the efficacy and safety of CHM on CHF based on syndrome differentiation. Methods/Design. This is a three-stage trial of CHM in the treatment of CHF. The first stage is a literature review aiming to explore the common syndromes of CHF. The second is a multicentral, randomized, placebo-controlled trial to evaluate the efficacy and safety of CHM for the treatment of CHF. The third is a multicentral, randomized controlled clinical trial aiming to make cost-effectiveness analysis and evaluate the feasibility, compliance, and universality of CHM on CHF. Discussion. This trial will evaluate the efficacy, safety, feasibility, compliance, and universality of CHM on CHF. The expected outcome is to provide evidence-based recommendations for CHM on CHF and develop a prescription of CHM in the treatment of CHF. This trial is registered with NCT01939236 (Stage Two of the whole trial). [ABSTRACT FROM AUTHOR]