Puerarin ameliorated pressure overload-induced cardiac hypertrophy in ovariectomized rats through activation of the PPARα/PGC-1 pathway.

Estrogen deficiency induces cardiac dysfunction and increases the risk of cardiovascular disease in postmenopausal women and in those who underwent bilateral oophorectomy. Previous evidence suggests that puerarin, a phytoestrogen, exerts beneficial effects on cardiac function in patients with cardiac hypertrophy. In this study, we investigated whether puerarin could prevent cardiac hypertrophy and remodeling in ovariectomized, aortic-banded rats. Female SD rats subjected to bilateral ovariectomy (OVX) plus abdominal aortic constriction (AAC). The rats were treated with puerarin (50 mg·kg-1 ·d-1, ip) for 8 weeks. Then echocardiography was assessed, and the rats were sacrificed, their heart tissues were extracted and allocated for further experiments. We showed that puerarin administration significantly attenuated cardiac hypertrophy and remodeling in AAC-treated OVX rats, which could be attributed to activation of PPARα/PPARγ coactivator-1 (PGC-1) pathway. Puerarin administration significantly increased the expression of estrogen-related receptor α, nuclear respiratory factor 1, and mitochondrial transcription factor A in hearts. Moreover, puerarin administration regulated the expression of metabolic genes in AAC-treated OVX rats. Hypertrophic changes could be induced in neonatal rat cardiomyocytes (NRCM) in vitro by treatment with angiotensin II (Ang II, 1 µM), which was attenuated by co-treatemnt with puerarin (100 µM). We further showed that puerarin decreased Ang II-induced accumulation of non-esterified fatty acids (NEFAs) and deletion of ATP, attenuated the Ang II-induced dissipation of the mitochondrial membrane potential, and improved the mitochondrial dysfunction in NRCM. Furthermore, addition of PPARα antagonist GW6471 (10 µM) partially abolished the anti-hypertrophic effects and metabolic effects of puerarin in NRCM. In conclusion, puerarin prevents cardiac hypertrophy in AAC-treated OVX rats through activation of PPARα/PGC-1 pathway and regulation of energy metabolism remodeling. This may provide a new approach to prevent the development of heart failure in postmenopausal women.

Glucagon-Like Peptide-1 Analog Liraglutide Attenuates Pressure-Overload Induced Cardiac Hypertrophy and Apoptosis through Activating ATP Sensitive Potassium Channels.

PURPOSE: This study aimed to investigate whether inhibition of glucagon-like peptide-1 (GLP-1) on pressure overload induced cardiac hypertrophy and apoptosis is related to activation of ATP sensitive potassium (KATP) channels. METHODS: Male SD rats were randomly divided into five groups: sham, control (abdominal aortic constriction), GLP-1 analog liraglutide (0.3 mg/kg/twice day), KATP channel blocker glibenclamide (5 mg/kg/day), and liraglutide plus glibenclamide. RESULTS: Relative to the control on week 16, liraglutide upregulated protein and mRNA levels of KATP channel subunits Kir6.2/SUR2 and their expression in the myocardium, vascular smooth muscle, aortic endothelium, and cardiac microvasculature. Consistent with a reduction in aortic wall thickness (61.4 ± 7.6 vs. 75.0 ± 7.6 µm, p < 0.05), liraglutide enhanced maximal aortic endothelium-dependent relaxation in response to acetylcholine (71.9 ± 8.7 vs. 38.6 ± 4.8%, p < 0.05). Along with a reduction in heart to body weight ratio (2.6 ± 0.1 vs. 3.4 ± 0.4, mg/g, p < 0.05) by liraglutide, hypertrophied cardiomyocytes (371.0 ± 34.4 vs. 933.6 ± 156.6 µm2, p < 0.05) and apoptotic cells (17.5 ± 8.2 vs. 44.7 ± 7.9%, p < 0.05) were reduced. Expression of anti-apoptotic protein BCL-2 and contents of myocardial ATP were augmented, and expression of cleaved-caspase 3 and levels of serum Tn-I/-T were reduced. Echocardiography and hemodynamic measurement showed that cardiac systolic function was enhanced as evidenced by increased ejection fraction (88.4 ± 4.8 vs. 73.8 ± 5.1%, p < 0.05) and left ventricular systolic pressure (105.2 ± 10.8 vs. 82.7 ± 7.9 mmHg, p < 0.05), and diastolic function was preserved as shown by a reduction of ventricular end-diastolic pressure (-3.1 ± 2.9 vs. 6.7 ± 2.8 mmHg, p < 0.05). Furthermore, left ventricular internal diameter at end-diastole (5.8 ± 0.5 vs. 7.7 ± 0.6 mm, p < 0.05) and left ventricular internal diameter at end-systole (3.0 ± 0.6 vs. 4.7 ± 0.4 mm, p < 0.05) were improved. Dietary administration of glibenclamide alone did not alter all the parameters measured but significantly blocked liraglutide-exerted cardioprotection. CONCLUSION: Liraglutide ameliorates cardiac hypertrophy and apoptosis, potentially via activating KATP channel-mediated signaling pathway. These data suggest that liraglutide might be considered as an adjuvant therapy to treat patients with heart failure.

Tongsaimai reverses the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats.

Treating ventricular remodeling continues to be a clinical challenge. Studies have shown that hypertension is one of the most common causes of ventricular remodeling, and is a major cause of cardiovascular risk in adults. Here, we report that Tongsaimai (TSM), a Chinese traditional medicine, could inhibit arterial pressure and left ventricular pressure to improve hemodynamic abnormalities in rats impaired by abdominal aortic constriction (AAC). Administration of TSM significantly reduced the heart mass index and the left ventricular mass index significantly in AAC rats. TSM could also markedly ameliorate cardiac collagen deposition and reduce the concentration of hydroxyproline in the heart of AAC rats. Moreover, TSM alleviated cardiac histomorphology injury resulting from AAC, including reducing cardiomyocyte hypertrophy, fibrous connective tissue hyperplasia, cardiomyocyte apoptosis, replacement fibrosis and the disorders of myocardial myofibrils, intercalated discs, mitochondria and mitochondrial crista. In addition, the levels of transforming growth factor (TGF) - ß and inflammation-related molecules including tumor necrosis factor-α (TNF-α), which were over-expressed with AAC, were decreased by STM. In conclusion, STM could reverse the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats.

Beneficial Effect of Silymarin in Pressure Overload Induced Experimental Cardiac Hypertrophy.

The present investigation was undertaken to study the effect of silymarin on cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) in Wistar rats. Silymarin was administered for 9 weeks at the end of which we evaluated hypertrophic, hemodynamic, non-specific cardiac markers, oxidative stress parameters, and determined mitochondrial DNA concentration. Hypertrophic control animals exhibited cardiac hypertrophy, altered hemodynamics, oxidative stress, and decreased mitochondrial DNA (mtDNA) concentration. Treatment with silymarin prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Docking studies revealed that silymarin produces maximum docking score with mitogen-activated protein kinases (MAPK) p38 as compared to other relevant proteins docked. Moreover, PAAC-control rats exhibited significantly increased expression of MAPK p38ß mRNA levels which were significantly decreased by the treatment of silymarin. Our data suggest that silymarin produces beneficial effects on cardiac hypertrophy which are likely to be mediated through inhibition of MAPK p38ß.

Sodium Butyrate Controls Cardiac Hypertrophy in Experimental Models of Rats.

The aim of the present research was to study the effect of sodium butyrate (SB) on partial abdominal aorta constriction (PAAC)-induced cardiac hypertrophy and determine its mechanism of action. Healthy Wistar rats were exposed to PAAC for eight weeks. After eight weeks, we carried out hypertrophic and hemodynamic evaluation and measured oxidative stress parameters and mitochondrial DNA concentration. PAAC control animals exhibited cardiac hypertrophy, decreased hemodynamic functions and oxidative stress. Treatment with SB reduced hypertrophic indices, LV wall thickness, LV collagen levels, cardiomyocyte diameter, serum lipid levels and serum cardiac biomarkers. Treatment with SB also improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies which revealed that SB decreases expression of prohypertrophic HDAC, i.e., HDAC2, without altering the expression of anti-hypertrophic HDAC5. Sodium butyrate produces beneficial effect on cardiac hypertrophy as is evident, specifically from reduction in hypertrophic parameters including collagen levels, improvement in mitochondrial DNA concentration and preservation of LV systolic and diastolic dysfunction. This beneficial effect of sodium butyrate is mediated through downregulation of class I HDACs, specifically HDAC2 without any effect on class II HDAC, i.e., HDAC5. Thus, selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors which are class I inhibitor and class II promoter can be designed to obtain a 'pan' or 'dual' natural HDAC 'regulators.'

Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy.

The regulatory paradigm in cardiac hypertrophy involves alterations in gene expression that is mediated by chromatin remodeling. Various data suggest that class I and class II histone deacetylases (HDACs) play opposing roles in the regulation of hypertrophic pathways. To address this, we tested the effect of magnesium valproate (MgV), an HDAC inhibitor with 5 times more potency on class I HDACs. Cardiac hypertrophy was induced by partial abdominal aortic constriction in Wistar rats, and at the end of 6 weeks, we evaluated hypertrophic, hemodynamic, and oxidative stress parameters, and mitochondrial DNA concentration. Treatment with MgV prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress, and increased mitochondrial DNA concentration. MgV treatment also increased the survival rate of the animals as depicted by the Kaplan-Meier curve. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies, which revealed that MgV decreases expression of pro-hypertrophic HDAC (i.e., HDAC2) without altering the expression of anti-hypertrophic HDAC5. Selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors that are class I inhibitors and class II promoters can be designed to obtain "pan" or "dual" natural HDAC "regulators".

The effect of angoroside C on pressure overload-induced ventricular remodeling in rats.

BACKGROUND: Our previous study reveals that total rough extract of Radix Scrophulariae has a beneficial effect on ventricular remodeling. HYPOTHESIS: After carrying out a series of preliminary experiments, we speculated that angoroside C may be the effective agent. STUDY DESIGN: After oral administration, the effect of angoroside C on ventricular remodeling was evaluated by using a pressure-overloaded rat model, some related indexes were detected in vivo. METHODS: A model of pressure overloaded ventricular remodeling was produced by abdominal aortic constriction (AAC) in rats. The sham-operated rats underwent an identical surgical procedure except for AAC. AAC rats were randomly divided into five groups: model control group, three angoroside C treated groups (7.5, 15 and 30 mg·kg(-1)) and captopril treated group (40 mg·kg(-1)). The rats were orally administered with the corresponding drugs or drinking water for 4 weeks. The levels of blood pressure (BP), left ventricular weight index (LVWI) and heart weight index (HWI) were detected. Myocardium tissue was stained with hematoxylin and eosin or picric acid/sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of angiotensin Ⅱ (Ang Ⅱ), hydroxyproline (Hyp), matrix metalloproteinase 2 (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in myocardium or serum were determined. Real-time RT-PCR was performed to detect the mRNA expressions of endothelin 1 (ET-1), transforming growth factor ß1 (TGF-ß1). RESULTS: Angoroside C significantly reduced the BP, LVWI and HWI, decreased the content of Ang Ⅱ, Hyp, diminished cross sectional area of cardiomyocytes and ameliorated collagen deposition. Additionally, it markedly reduced collagen I and III expressions and regulated matrix metalloproteinase-2, 9 and inhibitors of metalloproteinase expressions. Angoroside C also down regulated the gene expressions of ET-1 and TGF-ß1mRNA in myocardium. CONCLUSION: Angoroside C has beneficial effects against ventricular remodeling. The mechanism is likely to be related to decreasing the level of Ang Ⅱ, attenuating the mRNA expressions of ET-1 and TGF-ß1.

Beneficial role of tamoxifen in experimentally induced cardiac hypertrophy.

BACKGROUND: Protein kinase C (PKC) activation is associated with cardiac hypertrophy (CH), fibrosis, inflammation and cardiac dysfunction. Tamoxifen is a PKC inhibitor. Despite these, reports on effect of tamoxifen on cardiac hypertrophy are not available. Hence, we have investigated effect of tamoxifen (2mg/kg/day, po) on CH. METHODS: In isoproterenol (ISO) induced CH, ISO (5mg/kg/day, ip) was administered for 10 days in Wistar rats. For partial abdominal aortic constriction (PAAC), abdominal aorta was ligated by 4-0 silk thread around 7.0mm diameter blunt needle. Then the needle was removed to leave the aorta partially constricted for 30 days. Tamoxifen was given for 10 days and 30 days, respectively, in ISO and PAAC models and at end of each studies, animals were sacrificed and biochemical and cardiac parameters were evaluated. RESULTS: ISO and PAAC produced significant dyslipidemia, hypertension, bradycardia, oxidative stress and increase in serum lactate dehydrogenase and creatine kinase-MB, C-reactive protein. Treatment with tamoxifen significantly controlled dyslipidemia, hypertension, bradycardia, oxidative stress and reduced serum cardiac markers. ISO control and PAAC control rats exhibited significantly increased cardiac and left ventricular (LV) hypertrophic index, LV thickness, cardiomyocyte diameter. Treatment with tamoxifen significantly reduced these hypertrophic indices. There was a significant increase in LV collagen level, decrease in Na(+)K(+)ATPase activity, and reduction in the rate of pressure development and decay. Tamoxifen significantly reduced LV collagen, increased Na(+)K(+)ATPase activity and improved hemodynamic function. This was further supported by histopathological studies, in which tamoxifen showed marked decrease in fibrosis and increase in extracellular spaces in the treated animals. CONCLUSIONS: Our data suggest that tamoxifen produces beneficial effects on cardiac hypertrophy and hence may be considered as a preventive measure for cardiac hypertrophy.

Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy.

BACKGROUND: Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear. METHODS AND RESULTS: Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E'), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP. CONCLUSIONS: The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.