PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation

Abstract

Post‐menopausal women have a higher risk of developing cardiometabolic dysfunction. Atorvastatin attenuates dyslipidaemia and cardiac dysfunction but it can have undesirable effects including increased risk of diabetes and myalgia. Currently, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor efficiently reduces low‐density lipoprotein cholesterol (LDL‐C) levels more effectively than atorvastatin. We have been suggested that PCSK9 inhibitor attenuated cardiometabolic impairment more effectively than atorvastatin in ovariectomized prediabetic rats. Female Wistar rats (n = 48) were fed a normal diet (ND) or high‐fat diet (HFD) for 12 weeks. Then, HFD rats were assigned to a sham‐operated (Sham) or ovariectomized (OVX) group. Six weeks after surgery, the OVX group was subdivided into 4 treatment groups: vehicle (HFOV), atorvastatin (HFOA) (40 mg/kg/day; s.c.), PCSK9 inhibitor (HFOP) (4 mg/kg/day; s.c.) and oestrogen (HFOE 2 ) (50 µg/kg/day; s.c.) for an additional 3 weeks. Metabolic parameters, cardiac and mitochondrial function, and [Ca 2+ ] i transients were evaluated. All HFD rats became obese‐insulin resistant. HFS rats had significantly impaired left ventricular (LV) function, cardiac mitochondrial function and [Ca 2+ ] i transient dysregulation. Oestrogen deprivation (HFOV) aggravated all of these impairments. Our findings indicated that the atorvastatin, PCSK9 inhibitor and oestrogen shared similar efficacy in the attenuation in cardiometabolic impairment in ovariectomized prediabetic rats.

Effect of TLR4/MyD88/NF‐kB axis in paraventricular nucleus on ventricular arrhythmias induced by sympathetic hyperexcitation in post‐myocardial infarction rats

“…High frequency (HF; 0.75-2.5 Hz) indicates parasympathetic tone, while low frequency (LF; 0.05-0.75 Hz) indicates parasympathetic and sympathetic tone. An increased LF/HF ratio indicates cardiac sympathetic imbalance 6,19.…”

Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin–Mediated Mitophagy

“… 38 In addition, the inhibition of PCSK9 has demonstrated a protective effect on mitochondrial function in rats fed a high-fat diet. 39 , 40 We also observed a protective effect of PCSK9 inhibition on mitochondrial injury, highlighting the significant role of PCSK9 in mitochondrial dysfunction. However, the underlying mechanism by which PCSK9 exacerbates mitochondrial injury remains unknown.…”

Oestrogenic Regulation of Mitochondrial Dynamics

“…These abnormalities occurred in correlation with the impairment of mitochondrial function and dynamics, including mitochondrial fragmentation (due to upregulation of phosphorylated Drp1), increase in reactive oxygen species (ROS) production and higher sensitisation to MPTP stimuli. These effects were partially alleviated by the administration of E2 [143]. In addition, no changes were observed in the levels of mitochondrial fusion proteins, including Opa1, Mfn1 and Mfn2, which suggests preferential effects of E2 on mitochondrial fission in the setting of HFD-induced insulin resistance [143].…”

“…These effects were partially alleviated by the administration of E2 [143]. In addition, no changes were observed in the levels of mitochondrial fusion proteins, including Opa1, Mfn1 and Mfn2, which suggests preferential effects of E2 on mitochondrial fission in the setting of HFD-induced insulin resistance [143]. Moreover, E2 may participate in anti-thrombotic effects of Opa1.…”