Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes

Abstract

Statins, which reduce LDL-cholesterol by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are among the most widely prescribed drugs. Skeletal myopathy is a known statin-induced adverse effect associated with mitochondrial changes. We hypothesized that similar effects would occur in cardiac myocytes in a lipophilicity-dependent manner between 2 common statins: atorvastatin (lipophilic) and pravastatin (hydrophilic). Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48 h. Both statins induced endoplasmic reticular (ER) stress, but only atorvastatin inhibited ERK1/2, Akt, and mammalian target of rapamycin signaling; reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor, and insulin receptor-β; decreased Ras homolog gene family, member A activation; and induced apoptosis. In cardiomyocyte-equivalent HL-1 cells, atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption. When male mice underwent atorvastatin and pravastatin administration per os for up to 7 mo, only long-term atorvastatin, but not pravastatin, induced elevated serum creatine kinase; swollen, misaligned, size-variable, and disconnected cardiac mitochondria; alteration of ER structure; repression of mitochondria- and endoplasmic reticulum-related genes; and a 21% increase in mortality in cardiac-specific vinculin-knockout mice during the first 2 months of administration. To our knowledge, we are the first to demonstrate in vivo that long-term atorvastatin administration alters cardiac ultrastructure, a finding with important clinical implications.-Godoy, J. C., Niesman, I. R., Busija, A. R., Kassan, A., Schilling, J. M., Schwarz, A., Alvarez, E. A., Dalton, N. D., Drummond, J. C., Roth, D. M., Kararigas, G., Patel, H. H., Zemljic-Harpf, A. E. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.

The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes

“…It is important to mention that a possible limitation of this study are the potential interactions, synergisms, or detriments that may arise when studying or implementing novel drugs like SS-31 in a background affected by other medications such as statins. In this sense, previous research has stated that statins can have both detrimental [63,64,65,66] and beneficial effects [67,68,69,70,71,72,73,74,75,76,77], often unrelated to their lipid-lowering effect and rather associated with their pleiotropic actions. The variation of the effect is explained by the type of statin, the dose, the combination with other treatments and the experimental model.…”

Pravastatin and Gemfibrozil Modulate Differently Hepatic and Colonic Mitochondrial Respiration in Tissue Homogenates from Healthy Rats

“…Kaufmann et al [13] did not observe any effects of pravastatin on mitochondrial oxygen consumption in isolated muscle mitochondria in vitro using similar pravastatin concentrations (50–400 µM). Godoy et al [1] tested the influence of atorvastatin and pravastatin (10 µM) on HL-1 cardiomyocyte mitochondrial function and could show, that atorvastatin altered mitochondrial function compared to cardiomyocytes treated with pravastatin. The difference between our results (declined mitochondrial respiration in liver) and the other findings (unchanged mitochondrial respiration) could be caused by many factors like different experimental conditions (in vitro vs. ex vivo, different drug concentrations in in vitro experiments and oral pretreatment), long-term therapy vs. single dose and different tissues (liver, muscle, cardiomyocytes).…”

“…Statins are among the most widely prescribed drug classes in the world. They are used to lower low density lipoprotein-cholesterol (LDL-C) serum levels in patients for the prevention and treatment of cardiovascular diseases [1]. They exhibit a wide range of effects: additionally to the inhibition of cholesterol synthesis, they modulate inflammatory response, affect coagulation system, induce apoptosis and decrease oxidative stress [2].…”

“…Hydrophilic statins (e.g., pravastatin) are considered as less ‘mitotoxic’ compared to lipophilic statins such as cerivastatin, fluvastatin, atorvastatin and simvastatin [13]. Even if some authors failed to show any effects of pravastatin on mitochondrial respiration in muscle [13], in the liver [16] and in HL-1 cardiomyocytes [1], cases of drug induced hepatotoxicity are reported [17]. Furthermore, evidence exists for even positive effects of statins on mitochondrial function.…”

Statins and autoimmunity: State-of-the-art

“…Simvastatin combined with ezetimibe reduced LFA-1 gene expression. LFA-1 is an essential costimulator for migration and trafficking of T-cells, and various studies confirmed the inhibitory effects of statins on this molecule (Godoy et al, 2018;McInnes & Schett, 2011;Tang et al, 2011). Additionally, both atorvastatin and simvastatin interfere with Th1 cell migration by inhibiting the CD40/CD40L-associated activation of B-lymphocytes (Shimabukuro-Vornhagen et al, 2014).…”