Cytosolic H₂O₂ mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload

Abstract

Cohen RA, Colucci WS. Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload. Am J Physiol Heart Circ Physiol 306: H1453-H1463, 2014. First published March 14, 2014 doi:10.1152/ajpheart.00084.2014.-Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity. apoptosis; catalase; H2O2; hypertrophy; SERCA THE ROLE OF REACTIVE OXYGEN species (ROS) in mediating myocardial failure in response to chronic hemodynamic overload is well appreciated (29,32,34). Systemic administration of small molecule antioxidants ameliorated pathological remodeling and failure in mice with hemodynamic overload due to chronic aortic constriction (8,35). Transgenic total body overexpression of mitochondrial catalase (mCAT) likewise decreased left ventricular (LV) hypertrophy and failure in mice with aortic constriction (6), further suggesting that mitochondria are a source of ROS in hemodynamic overload. However, several nonmitochondrial sources of ROS in the myocardium have been implicated in hemodynamic overload including uncoupled endothelial nitric oxide synthase (23, 33), NADPH oxidases (4), and xanthine oxidase (21). Because these nonmitochondrial sources of ROS are located in the sarcoplasm, we reasoned that their effects should be susceptible to catalase that is targeted to the sarcoplasm of the cardiac myocyte. Accordingly, our first goal was to test whether LV hypertrophy and failur...

A change of heart: oxidative stress in governing muscle function?

“…Interestingly, oxidative stress was found to cause an irreversible oxidation of Cys674 to sulfonic acid, thus impairing NOinduced relaxation through the prevention of reversible Sglutathionylation and activation of SERCA in diseased muscles (Cohen and Adachi 2006;Adachi et al 2007). Similar findings were observed in a study in which oxidative stress decreased activity of SERCA via oxidative modifications of Cys674 and Tyr294/295 (Qin et al 2014). Taken together, these findings suggest that reduced activity of SERCA due to oxidative stress and the simultaneously increased activity of RyR2 and LTCC could result in diastolic Ca 2+ overload, which might in turn lead to slow myocyte relaxation and diastolic dysfunction.…”

Inhibition of Cardiomyocytes Hypertrophy by Resveratrol Is Associated with Amelioration of Endoplasmic Reticulum Stress

“…A recent study showed that Res may attenuate left ventricular hypertrophy via inhibiting NFAT-dependent transcription and suppress heart failure and reverse myocardial remodeling [21,22]. Res treatment may inhibit high blood pressure and attenuate apoptosis of ventricular myocytes and improve ventricular function [23,24]. In this study, we investigated that the effects of Res treatment on myocardial hypertrophy induced by ISO.…”

Resveratrol Attenuated Low Ambient Temperature-Induced Myocardial Hypertrophy via Inhibiting Cardiomyocyte Apoptosis

“…Then, the decline of heart functions including EF and LVIDd in mice with cold stress was partially restored by Resveratrol treatment. Lots of studies have reported that cardiomyocyte apoptosis was associated with myocardial remodeling in heart diseases [32]. We found that Resveratrol treatment also inhibited the apoptosis of cardiomyocytes of cold-treated mice.…”

“…Previous studies have showed that apoptosis of cardiomyocytes was involved in cardiac remodeling in some heart diseases [32]. So we further investigate if cardiomyocyte apoptosis is also related to the changes of myocardial remodeling in cold-treated mice.…”

“…Homocysteine-induced apoptosis of ventricular myocytes was also attenuated by Resveratrol treatment [33]. Oral supplement with 100mg/kg/day of Resveratrol may improve ventricular function and increase blood flow to the myocardium remote from an area of ischemia [32]. In this study, we investigated the effects of Resveratrol (100mg/kg/day) treatment on myocardial hypertrophy induced by cold exposure.…”