Bawei Chenxiang Wan ameliorates right ventricular hypertrophy in rats with high altitude heart disease by SIRT3-HIF1α-PDK/PDH signaling pathway improving fatty acid and glucose metabolism

Abstract

Background Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, it is unknown whether it confer protection through right ventricle (RV) myocardial metabolic mechanism. Methods Male Sprague–Dawley rats were oral administration BCW, injected concurrently with a bolus of Sugen5416 (SU5416) and hypoxia exposure (5000m altitude) for 4 weeks(SuHx). Right ventricular hypertrophy (RVH) in high altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle (LV) +septum weights) and heart weight to body weight ratio (HW/BW). The effect of therapeutic administration of BCW in the RVH on hemodynamics assessed by catheterization [right ventricular and Pulmonary artery pressure (mRVP and mPAP, respectively)]. Tissue samples were used to perform a histological staining, mRNA and protein levels confirmatory analyses to identify altered the mechanisms within the RVH in HAHD. Further verify the protective mechanism of BCW was studied in cell culture. Results BCW significantly reduced SuHx-associated RVH, indicated by macro morphology, HW/BW ratio, Fulton index, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and the myocardial enzymes. Moreover, BCW can also alleviate the disorder of glucose and fatty acid metabolism by up-regulating carnitine palmitoyltransferase1ɑ (CPT1ɑ), citrate synthase (CS), acetyl-CoA, down-regulating glucose transport-4 (GLUT-4), Phosphofructokinase (PFK), pyruvate, resulting in the reduction of Free fatty acids (FFA), lactic acid (LD) and the increase of aerobic oxidation. This process may be mediated by regulating sirtuin3 (SIRT3)-Hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase(PDK)/pyruvate dehydrogenase (PDH) signaling pathways. Subsequently, inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) significantly can reverse the anti-RVH in HAHD effect of BCW indicated by hypertrophy markers and serum myocardial enzyme levels. Conclusions In conclusion, BCW prevents SuHx-induced RVH in HAHD by SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.