The Influence of Statins on the Aerobic Metabolism of Endothelial Cells

Izabela Broniarek,Wieslawa Jarmuszkiewicz,Lukasz Galganski,Karolina Dominiak

doi:10.3390/ijms21041485

Izabela Broniarek, Wieslawa Jarmuszkiewicz + Show 2 more

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https://doi.org/10.3390/ijms21041485

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Abstract

Endothelial mitochondrial dysfunction is considered to be the main cause of cardiovascular disease. The aim of this research was to elucidate the effects of cholesterol-lowering statins on the aerobic metabolism of endothelial cells at the cellular and mitochondrial levels. In human umbilical vein endothelial cells (EA.hy926), six days of exposure to 100 nM atorvastatin (ATOR) induced a general decrease in mitochondrial respiration. No changes in mitochondrial biogenesis, cell viability, or ATP levels were observed, whereas a decrease in Coenzyme Q10 (Q10) content was accompanied by an increase in intracellular reactive oxygen species (ROS) production, although mitochondrial ROS production remained unchanged. The changes caused by 100 nM pravastatin were smaller than those caused by ATOR. The ATOR-induced changes at the respiratory chain level promoted increased mitochondrial ROS production. In addition to the reduced level of mitochondrial Q10, the activity of Complex III was decreased, and the amount of Complex III in a supercomplex with Complex IV was diminished. These changes may cause the observed decrease in mitochondrial membrane potential and an increase in Q10 reduction level as a consequence, leading to elevated mitochondrial ROS formation. The above observations highlight the role of endothelial mitochondria in response to potential metabolic adaptations related to the chronic exposure of endothelial cells to statins.

Highlights

Statins, the most widely prescribed medication worldwide, are cholesterol-lowering drugs that effectively reduce the risk of major cardiovascular events [1,2]
Since the observed effects caused by ATOR were stronger than those caused by PRAV, in further studies we focused on the influence of ATOR on the functioning of mitochondria in endothelial cells cultured in the presence of this statin
In ATOR-treated endothelial cells, the reduction in aerobic glucose oxidation was accompanied by decreased anaerobic glycolysis and unchanged mitochondrial biogenesis

Summary

Introduction

The most widely prescribed medication worldwide, are cholesterol-lowering drugs that effectively reduce the risk of major cardiovascular events [1,2]. Statins inhibit endogenous cholesterol synthesis, as well as the synthesis of mevalonate, a precursor to heme a (a structural part of cytochrome c oxidase (COX) Complex IV (CIV)) and Coenzyme Q10 (Q10, or ubiquinone), which are obligatory components of the mitochondrial electron transport chain. It is proposed that statins may damage mitochondria by inhibiting mitochondrial respiratory chain complexes, increasing mitochondrial ROS (mROS) formation and inducing the mitochondrial apoptosis pathway [10]. It has been shown that statin-induced myopathy is associated with mitochondrial Complex III (CIII) inhibition at the Qo binding site [4]. The mechanism of statin-induced mitochondrial dysfunction is complex and not fully understood, especially in tissues other than muscle, including vascular endothelium

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