Atorvastatin reverses high cholesterol‐induced cardiac remodelling and regulates mitochondrial quality‐control in a cholesterol‐independent manner: An experimental study

Abstract

Mitochondria are key regulators of cell fate, maintaining self‐stability by a fine‐tuned quality‐control network including mitophagy, biogenesis, fission and fusion processes. Myocardial mitochondria can be impaired by hypercholesterolemia. Statins, such as atorvastatin, are considered the cornerstone in the management of hypercholesterolaemia primarily due to their marked cholesterol‐lowering ability. The direct effect of atorvastatin on myocardial mitochondria remains unclear. We aimed to explore whether atorvastatin could attenuate myocardial mitochondrial defects induced by high cholesterol, and whether cycloastragenol, a potent telomerase activator, could be used as a potential complementary bioactive compound for obesity and hypercholesterolaemia treatment. We found that atorvastatin at a low dose (3 mg/kg) did not reduce elevated serum cholesterol, but reversed cardiac remodelling and dysfunction in C57BL/6J mice fed with high‐fat diet (HFD). Atorvastatin reversed the upregulated mitophagy, mitochondrial fission and fusion, accompanied by mitochondrial biogenesis activation in HFD‐fed mice hearts. Mitochondrial structural impairments were attenuated by atorvastatin in HFD‐fed mice and oxidized low‐density lipoprotein (ox‐LDL) exposed HL‐1 cardiomyocytes. The depolarized mitochondrial membrane potential and increased mitochondrial oxygen consumption rates in ox‐LDL exposed HL‐1 cells were recovered by atorvastatin. Furthermore, atorvastatin co‐treated with cycloastragenol had better effects on reducing body weight, improving cardiac remodelling and dysfunction, and protecting mitochondria in high cholesterol. Conclusively, low‐dose atorvastatin exhibited a cholesterol‐independent cardioprotective effect through improving the mitochondrial quality‐control network and repairing mitochondrial ultrastructure in high cholesterol. Atorvastatin plus cycloastragenol supplement therapy has a better effect on treating obesity and hypercholesterolaemia.

Association of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 With Angiotensin II Type 1 Receptor Impacts Mitochondrial Quality Control, Offering Promise for the Treatment of Vascular Senescence

“…Regardless of mitochondrial dynamics, there were some reports of mitochondrial fission induced by ox-LDL or a high-fat diet in various cells or animals. Treatment with ox-LDL induces excessive mitochondrial fission in rat annulus fibrosus cells ( 24 ) and the hearts of high-fat-fed C57BL/6 mice showed mitochondrial fission ( 17 ). As shown in Figure 4 , ox-LDL activated CRAF, MEK, and ERK.…”

“…However, there are few reports on the relationship between the recovery of mitochondrial function from the effects AT1R inhibition and mitochondrial quality control through mitochondrial dynamics and autophagy. While the administration of ox-LDL decreased mitochondrial function in HL-1 cells, there is no report that this mitochondrial dysfunction is ameliorated by AT1R inhibition in terms of mitochondrial dynamics and autophagy ( 17 ). Therefore, we hypothesized that (1) the association of LOX-1 and AT1R is involved in mitochondrial quality control through mitochondrial dynamics and autophagy, and (2) AT1R inhibition using ARB, Candesartan, may ameliorate ox-LDL-mediated senescence, leading to atherosclerosis.…”

Hesperidin, vanillic acid, and sinapic acid attenuate atorvastatin‐induced mitochondrial dysfunction via inhibition of mitochondrial swelling and maintenance of mitochondrial function in pancreas isolated mitochondria

“…However, beneficial effects of atorvastatin on mitochondria and oxidative stress as an antioxidant have been reported in previous studies (Devasani et al, 2020; Jia et al, 2021). But it seems that the dose of atorvastatin has an effect in creating these contradictory effects (Wang, Chang, et al, 2014; Zheng et al, 2021), so that it is associated with beneficial effects on mitochondria and oxidative stress at low doses, while it can be associated with deleterious effects on these organelles at high doses and long‐term use (Jiménez‐Santos et al, 2014).…”