PCSK9 inhibitor effectively attenuates cardiometabolic impairment in obese-insulin resistant rats

Abstract

© 2020 Elsevier B.V. Long-term high-fat diet consumption causes obese-insulin resistance and cardiac mitochondrial dysfunction, leading to impaired left ventricular (LV) function. Atorvastatin effectively improved lipid profiles in obese patients. However, inadequate reduction in low density lipoprotein cholesterol (LDL-C) level was found. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor effectively reduced LDL-C levels. We hypothesized that this PCSK9 inhibitor has a greater efficacy in attenuating cardiometabolic impairments than atorvastatin in obese-insulin resistant rats. Female rats were fed with either a high fat or normal diet for 12 weeks. High fat diet fed rats (HFD) were then divided into 3 groups and were given vehicle, atorvastatin (40 mg/kg/day; s.c.), or PCSK9 inhibitor (4 mg/kg/day; s.c.) for additional 3 weeks. The metabolic parameters, cardiac and mitochondrial function and [Ca2+]i transients were determined. HFD rats developed obese-insulin resistance as indicated by increased plasma insulin and HOMA index. Although high-fat diet fed rats treated with vehicle (HFV) rats had markedly impaired LV function as indicated by reduced %LVFS, impaired cardiac mitochondrial function, and [Ca2+]i transient regulation, these impairments were attenuated in high-fat diet fed rats treated with atorvastatin (HFA) and high-fat diet fed rats treated with PCSK9 inhibitor (HFP) rats. However, these improvements were greater in HFP rats than HFA rats. Our findings indicated that the PCSK9 inhibitor exerted greater cardioprotection than atorvastatin through improved mitochondrial function in obese-insulin resistant rats.