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Abstract: Ursolic acid is reported to have beneficial effects on the regulation of cardiovascular homeostasis. However, the effects of ursolic acid on cardiac hormone secretion are yet to be defined. The present study was designed to test the effects of ursolic acid on the secretory and contractile functions of the atria. Experiments were conducted in isolated perfused beating rabbit atria. We measured the changes in atrial dynamics, pulse pressure, stroke volume, cAMP efflux, as well as the secretion of atrial natriuretic peptide (ANP). Ursolic acid increased ANP secretion and mechanical dynamics in a concentration-dependent manner. The inhibition of L-type Ca2+ channels with nifedipine attenuated the ursolic acid-induced increase in ANP secretion but not mechanical dynamics. The inhibition of K+ ATP channels with glibenclamide attenuated the ursolic acid-induced increase in ANP secretion—but not atrial dynamics—in a concentration-dependent manner. The selective Na+–K+-ATPase inhibitor ouabain blocked the ursolic acid-induced increase in atrial dynamics but not ANP secretion. These findings show that ursolic acid increases ANP secretion via its activation of K+ ATP channels and subsequent inhibition of Ca2+ entry through L-type Ca2+ channels in rabbit atria. These data also suggest that ursolic acid increases atrial dynamics via its inhibition of Na+–K+-ATPase activity. [ABSTRACT FROM AUTHOR]

Abstract: To investigate the mechanism of action by which a new anti-inflammatory active compound, 1-O-acetylbritannilactone (ABL) isolated from Inula britannica-F., inhibits inflammatory responses in vascular smooth muscle cells (VSMCs). Enzyme immunoassay was used to measure the levels of prostandin E2 (PGE2) production. Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor-κB (NF-κB) p65 and the expression of IκB-α, pIκB-α and cyclooxygenase-2 (COX-2). Electrophoretic mobility shift assays (EMSA) were used to detect DNA-binding activity of NF-κB in VSMCs. ABL (5, 10, 20 μmmol/l) had several concentration-dependent effects, including inhibition of lipopolysaccharide (LPS)-induced PGE2 production and COX-2 expression, and blockade of NF-κB activation and translocation. These effects were owing to reductions in IκB-α phosphorylation and degradation induced by LPS. In addition, ABL directly inhibited the binding of active NF-κB to specific DNA cis-element. These results indicate that ABL is a potent inhibitor of LPS-stimulated VSMC inflammatory responses through blockade of NF-κB activity and inhibition of inflammatory gene COX-2 expression. [Copyright &y& Elsevier]

cAMP is known to control the release of atrial natriuretic peptide. To define the roles of cyclic nucleotide phosphodiesterase subtypes in the regulation of atrial natriuretic peptide (ANP) release, experiments were done with perfused beating rabbit atria. Phosphodiesterase 3 subtype-specific inhibitors, milrinone and cilostamide, inhibited myocytic ANP release with a concomitant increase in cAMP efflux. Similarly, trequinsin, another phosphodiesterase 3 inhibitor, decreased ANP release. A phosphodiesterase 4 subtype-specific inhibitor, rolipram, did not significantly change ANP release but increased AMP efflux. Also, 4-[(3-butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone (Ro 20-1724), another phosphodiesterase 4 inhibitor, did not significantly change ANP release. The cAMP efflux was higher in the atrium treated with rolipram than in the atrium treated with milrinone or cilostamide. The data show that the cAMP pool, which is metabolized by phosphodiesterase 3, but not phosphodiesterase 4, is closely related to the basal regulation of atrial ANP release. The results suggest that intracellular cAMP is compartmentalized in the regulation of atrial ANP release, and that the release is controlled by a phosphodiesterase subtype-specific mechanism. [Copyright &y& Elsevier]

High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. Palmitic acid (PA), a free fatty acid, is the main component of dietary saturated fat. Physcion, a chemical ingredient from Rhubarb, has been shown anti-hypertensive, anti-bacteria, and anti-tumor properties. However, the effects of physcion on endothelial dysfunction under HFD-induced obesity have not been reported. The purpose of the present study was to define the protective effect of physcion on HFD-induced endothelial dysfunction and its mechanisms involved. Obesity rat model was induced by HFD for 12 weeks. A rat thoracic aortic ring model was used to investigate the effects of physcion on HFD-induced impairment of vasorelaxation. Endothelial cell injury model was constructed in human umbilical vein endothelial cells (HUVECs) by treating with PA (0.25 mM) for 24 h. The results revealed that physcion reduced body weight and the levels of plasma TG, prevented impairment of endothelium-dependent relaxation in HFD-fed rats. In PA-injured HUVECs, physcion inhibited impaired viability, apoptosis and inflammation. Physcion also suppressed PA-induced both oxidative stress and ER stress in HUVECs. Furthermore, physcion increased PA-induced decrease in the activation of eNOS/Nrf2 signaling in HUVECs. These findings suggest that physcion has a significant beneficial effect on regulating HFD-induced endothelial dysfunction, which may be related to the inhibition of oxidative stress and ER stress through activation of eNOS/Nrf2 signaling pathway. [Display omitted] • Physion inhibits HFD-induced endothelial dysfunction in rats. • Physion attenuates PA-induced endothelial cell apoptosis and inflammation. • eNOS/Nrf2 signaling involves in protection of physion. [ABSTRACT FROM AUTHOR]

Elevated levels of plasma homocysteine (Hcy) causes severe cardiac dysfunction, which is closely associated with oxidative stress. Emodin, a naturally occurring anthraquinone derivative, has been shown to exert antioxidant and anti-apoptosis activities. However, whether emodin could protect against Hcy-induced cardiac dysfunction remains unknown. The current study aimed to investigate the effects of emodin on the Hcy-induced cardiac dysfunction and its molecular mechanisms. Rats were fed a methionine diet to establish the animal model of hyperhomocysteinemia (HHcy). H9C2 cells were incubated with Hcy to induce a cell model of Hcy-injured cardiomyocytes. ELISA, HE staining, carotid artery and left ventricular cannulation, MTT, fluorescence staining, flow cytometry and western blotting were used in this study. Emodin significantly alleviated the structural damage of the myocardium and cardiac dysfunction from HHcy rats. Emodin prevented apoptosis and the collapse of MMP in the Hcy-treated H9C2 cells in vitro. Further, emodin reversed the Hcy-induced apoptosis-related biochemical changes including decreased Bcl-2/Bax protein ratio, and increased protein expression of Caspase-9/3. Moreover, emodin suppressed oxidative stress in Hcy-treated H9C2 cells. Mechanistically, emodin significantly inhibited the Hcy-activated MAPK by reducing ROS generation in H9C2 cells. Furthermore, emodin upregulated NO production by promoting the protein phosphorylation of Akt and eNOS in injured cells. The present study shows that emodin protects against Hcy-induced cardiac dysfunction by inhibiting oxidative stress via MAPK and Akt/eNOS/NO signaling pathways. [Display omitted] • Emodin prevents homocysteine-induced cardiac dysfunction in rats. • Emodin inhibits homocysteine-induced cardiomyocyte apoptosis. • Emodin attenuates homocysteine-activated MAPK signaling by suppressing ROS production in cardiomyocyte. • Activation of Akt/eNOS/NO pathway involves in cardiomyocyte protection of emodin against homocysteine. [ABSTRACT FROM AUTHOR]

Abstract: Emodin, an active anthraquinone constituent isolated from the rhubarb, a traditional Chinese herbal medicine which is widely used in clinical treatment, has cardiovascular protective properties. However, it remains unclear whether the cardiovascular protective actions of emodin are related to an activation of cardiac natriuretic hormone secretion. The purpose of the present study was to explore the effect of emodin on the secretion of ANP, a member of the family of cardiac natriuretic hormones, and its mechanisms involved. Experiments were performed in isolated perfused beating rabbit atria allowing measurement of ANP secretion, atrial pulse pressure, and stroke volume. Emodin increased ANP secretion concomitantly with a decrease in atrial pulse pressure and stroke volume in a concentration-dependent manner. These effects were reversible. Inhibition of K+ channels with tetraethylammonium and glibenclamide attenuated the emodin-induced changes in ANP secretion and atrial dynamics. Furthermore, the emodin-induced changes in ANP secretion and atrial dynamics were attenuated by inhibition of L-type Ca2+ channels with nifedipine. Atropine, methoctramine, tertiapin-Q, and pertussis toxin had no significant effect on the emodin-induced changes in ANP secretion and mechanical dynamics. The present study demonstrates that emodin increases ANP secretion via inhibition of L-type Ca2+ channels through an activation of K+ ATP channel in isolated beating rabbit atria. The results also provide a rationale for the use of emodin in the treatment of impairment of the regulation of the cardiovascular homeostasis. [Copyright &y& Elsevier]

Abstract: Intermedin is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family peptide, which has vasodilatory and hypotensive actions identical to those of adrenomedullin and CGRP. Cleavage sites located between 2 basic amino acids at Arg93–Arg94 result in the production of prepro-intermedin95–147, namely intermedin1–53. The bioactive action of intermedin1–53 and its physiological significance are unclear. In this work, we aimed to explore the effects of intermedin1–53 on acute myocardial injury induced by isoproterenol. Myocardial ischemia injury in rats was induced by subcutaneous injection of a high dose of isoproterenol, and the therapeutic effect of intermedin1–53 was observed. Plasma lactate dehydrogenase activity, myocardial and plasma malondialdehyde content were higher in the isoproterenol group than that in controls. Isoproterenol-treated rats showed lower maximal rate of increase and decrease of left-ventricle pressure development (±left-ventricle dp/dt max) and higher left-ventricle end-diastolic pressure (all P <0.01), which suggested severe heart failure and myocardial injury. Semi-quantitative RT-PCR analysis showed that the gene expression of calcitonin receptor-like receptor and receptor-activity-modifying protein (RAMP)1, RAMP2 and RAMP3 in ventricular myocardia were up-regulated by 79% (P <0.01), 48% (P <0.01), 31% (P <0.05) and 130% (P <0.01), respectively, compared with controls. In myocardial sarcolemmal membranes, the maximum binding capacity for [125I]-intermedin1–53 was increased by 118% (P <0.01) in the isoproterenol group compared with controls. Rats treated with low dosage intermedin1–53 (5 nmol/kg/day, 2 days) showed 21% (P <0.05) higher myocardial cAMP content, 18% and 31% higher + left-ventricle dp/dt max and -left-ventricle dp/dt max respectively, 288% lower left-ventricle end-diastolic pressure (all P <0.01), and attenuated myocardial lactate dehydrogenase leakage and malondialdehyde formation (all P <0.01). Treatment with high dosage intermedin1–53 (20 nmol/kg/day, 2 days) gave better results than that with low dosage intermedin1–53. These results suggest that the intermedin receptor system was up-regulated in isoproterenol-induced myocardial ischemic injury and intermedin1–53 might play a pivotal cardioprotective role in such injury. [Copyright &y& Elsevier]

The inflammation and proliferation of vascular smooth muscle cells (VSMCs) are the basic pathological feature of proliferative vascular diseases. Tanshinone ⅡA (Tan ⅡA), which is the most abundant fat-soluble element extracted from Salvia miltiorrhiza , has potent protective effects on the cardiovascular system. However, the underlying mechanism is still not fully understood. Here, we show that Tan ⅡA significantly inhibits neointimal formation and decreases VSMC inflammation by upregulating the expression of KLF4 and inhibiting the activation of NFκB signaling. Using a microRNA array analysis, we found that miR-712-5p expression is significantly upregulated in tumor necrosis factor alpha (TNF-α)-treated VSMCs. Loss- and gain-of-function experiments revealed that transfection of miR-712-5p mimic promotes, whereas depletion of miR-712-5p suppresses TNF-α-induced VSMC inflammation, leading to amelioration of intimal hyperplasia induced by carotid artery ligation. Moreover, depletion of miR-712-5p by its antagomir largely abrogates TNF-α-induced VSMC proliferation. Our findings suggest that miR-712-5p mediates the stimulatory effect of TNF-α on VSMC inflammation, and that Tan ⅡA inhibits VSMC inflammation and proliferation in vivo and in vitro by suppression of miR-712-5p expression. Targeting miR-712-5p may be a novel therapeutic strategy to prevent proliferative vascular diseases. • Tanshinone IIA inhibits VSMC inflammation and proliferation by suppression of miR-712-5p expression. • miR-712-5p mediated the stimulatory effect of TNF-α on VSMC inflammation. • Targeting miR-712-5p may be a novel therapeutic strategy to prevent proliferative vascular diseases. [ABSTRACT FROM AUTHOR]

Obesity is one of the main causes of human cardiovascular and cerebrovascular diseases. Baicalin, a bioactive flavonoid isolated from the herbal medicine Scutellaria baicalensis Georgi, is reported to ameliorate obesity and hyperlipidemia. However, its mechanism remains unclear. Here, we used network pharmacology to explore the potential mechanism of baicalin on a system level. First, we predicted the targets of baicalin and diseases, and then protein-protein interaction (PPI) networks were constructed. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server. Lastly, we confirmed the results of the network analysis by palmitic acid (PA) treated human hepatoma cells (HepG2) in vitro. The results indicated that 37 targets related to obesity treated by baicalin were predicted by network pharmacology, and top 10 related pathways were extracted by the KEGG database. Baicalin treatment could reduce triglyceride (TG) contents and lipid droplet accumulation in PA-treated HepG2 cells. The anti-obesity effects of baicalin might be due to the up-regulation of solute carrier family 2 member 1 (SLC2A1) and down-regulation of tumor necrosis factor (TNF), nuclear factor kappa B subunit 1 (NFKB1), sterol regulatory element binding transcription factor 1 (SREBF1), peroxisome proliferator activated receptor gamma and caspase 3 (CASP3). Our results indicated that baicalin may regulate key inflammatory markers, adipogenesis process, and apoptosis for treatment of obesity. [ABSTRACT FROM AUTHOR]

Homocysteine (Hcy) is an independent risk factor in the development of cardiovascular diseases (CVD). Hyperhomocysteinemia (HHcy), induces the injury of vascular endothelial cells via oxidative stress. Oxymatrine (OMT), one of the main components of Sophora flavescens , has displayed anti-inflammatory, anti-oxidant and anti-apoptotic activity. However, the effect of OMT on the Hcy-induced endothelial injury is not clearly defined yet. The aim of this study was to determine the protective effect of OMT on the Hcy-induced endothelial injury and its mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were cultured in vitro. Methyl thiazolyl tetrazolium assay (MTT), fluorescence staining, flow cytometry and western blotting were used in this study. OMT prevented the Hcy-induced toxicity and apoptosis in HUVECs. Moreover, OMT suppressed Hcy-induced increases in reactive oxygen species, lactate dehydrogenase, malondialdehyde levels and increased superoxide dismutase levels. OMT reversed the Hcy-induced decrease in the protein expression of nuclear factor erythroid-2-related factor 2 (Nrf2). In addition, OMT reversed the Hcy-induced apoptosis related biochemical changes such as decreased mitochondrial membrane potential and Bcl-2/Bax protein ratio, and increased protein expression of caspase-9 and caspase-3. Furthermore, OMT elevated the phosphorylation levels of Akt and eNOS, and the formation of nitric oxide (NO) in injured cells. These results suggest that OMT prevents Hcy-induced endothelial injury by regulating mitochondrial-dependent apoptosis and Akt-eNOS-NO signaling pathways concomitantly with accentuation of Nrf2 expression. Image 1 [ABSTRACT FROM AUTHOR]