The Influence of Statins on the Aerobic Metabolism of Endothelial Cells

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.

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

“…The same group further reported in the same in vitro experimental model that even lower concentrations of atorvastatin (100 nM) elicited a decrease in both maximal respiration (as result of supercomplexes rearrangement) and the total cellular coenzyme Q10 content [ 24 ]. Interestingly, these authors also reported a significant increase in the expression of UCP2 protein in mitochondria isolated from the endothelial cells exposed to 100 nM atorvastatin [ 25 ]. Vevera et al [ 11 ] showed in an in vivo study that 4-week treatment with simvastatin reduced platelet respiration in rats.…”

Improvement of Platelet Respiration by Cell–Permeable Succinate in Diabetic Patients Treated with Statins

“…Statins have been reported to cause uncoupling in rat myoblasts as shown by the pioneering work by Kaufmann et al [ 17 ]. More recently, Broniarek et al reported that atorvastatin (and, in some cases, pravastatin) causes uncoupling (increased LEAK respiration) in endothelial cells [ 52 ]. LEAK respiration is a dissipative component of mitochondrial respiration that is nonphosphorylating and determines heat production [ 26 , 27 ].…”

“…In our study, we did not find a significantly increased LEAK respiration between the statin–treated groups and the untreated controls in the experiments carried out in intact platelets. We speculate that the statin level in these patients was much lower as compared with the doses used in the majority of the ex vivo studies (up to 1000–fold higher than the plasma concentration of statins under therapeutic conditions) [ 17 , 34 , 35 , 52 , 53 ].…”

Simvastatin improves mitochondrial respiration in peripheral blood cells

“…Supercomplex formation is believed to be a very dynamic process and of great importance for regulation of mitochondrial respiration 42,43 . Recently, it has been demonstrated that endothelial cells changed their supercomplex formation in response to atorvastatin 44 . Supercomplex formation can be mediated by increased levels of ROS 45 .…”