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".

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.