دانلود رایگان مقاله انگلیسی پرواستاتین موثر در افزایش فاکتورهای خطر اما بی تاثیر در مقاومت موش های چاق در برابر ischaemic - الزویر 2018

Abstract

Statins are effective in management of dyslipidaemia, and a cornerstone of CVD prevention strategies. However, the impacts of their pleiotropic effects on other cardiovascular risk factors and myocardial responses to infarction are not well characterised. We hypothesised that pravastatin treatment in obesity improves lipid profiles, insulin-resistance and myocardial resistance to ischaemia/reperfusion (I/R) injury. Wistar rats were fed a control (C) chow or high carbohydrate and fat diet (HCFD) for 16 weeks with vehicle or pravastatin (prava 7.5 mg/kg/day) treatment for 8 weeks. At 16 weeks HOMAs were performed, blood samples collected and hearts excised for Langendorff perfusions/biochemical analyses. Antioxidant activity and proteins regulating mitochondrial fission/fusion and apoptosis were assessed. The HCFD increased body weight (736±15 vs. 655±12 g for C; P<0.001), serum triglycerides (2.91±0.52 vs. 1.64±0.26 mmol/L for C; P<0.001) and insulin-resistance (HOMA- 6.9±0.8 vs. 4.2±0.5 for C; P<0.05) while prava prevented diet induced changes and paradoxically increased lipid peroxidation. The HCFD increased infarct size (34.1±3.1% vs. 18.8±3.0% of AAR for C; P<0.05), which was unchanged by prava in C and HCFD animals. The HCFD decreased cardiac TxR activity and mitochondrial MFN-1 and increased mitochondrial DRP-1 (reducing MFN-1:DRP-1 ratio) and Bax expression, with the latter changes prevented by prava. While unaltered by diet, cytosolic levels of Bax and caspase-3 were reduced by prava in C and HCFD hearts (without changes in cleaved caspase-3). We conclude that obesity, hyper-triglyceridemia and impaired glycemic control in HCFD rats are countered by prava. Despite improved risk factors, prava did not reduce myocardial infarct size, potentially reflecting its complex pleiotropic impacts on cardiac GPX activity and MFN1, DRP-1, caspase-3 and Bcl-2 proteins.

5. Conclusions

The current study indicates that despite improvements in key systemic risk factors (including body weight, insulin-resistance and triglyceride levels), prava treatment failed to limit the exaggeration of myocardial infarction observed in dietary obesity with insulin-resistance. This increase in infarction in HCFD is consistent with impaired anti-oxidant activity, increased mitochondrial Bax, and increased fission (DRP-1) vs. fusion (MFN1) protein expression. The lack of a cardioprotective effect of prava may reflect diverse pleiotropic effects of the statin, which induced opposing changes in proteins governing apoptosis, fusion and fission, while suppressing cardiac GPX activity. The basis and impacts of these distinct molecular changes, which highlight the complexities of statin effects in healthy and diseased hearts, warrant further study.