Molecular Medicine Sex Differences in the Phosphorylation of Mitochondrial Proteins Result in Reduced Production of Reactive Oxygen Species and Cardioprotection in Females
نویسندگان
چکیده
Rationale: Although premenopausal females have a lower risk for cardiovascular disease, the mechanism(s) are poorly understood. Objective: We tested the hypothesis that cardioprotection in females is mediated by altered mitochondrial protein levels and/or posttranslational modifications. Methods and Results: Using both an in vivo and an isolated heart model of ischemia and reperfusion (I/R), we found that females had less injury than males. Using proteomic methods we found that female hearts had increased phosphorylation and activity of aldehyde dehydrogenase (ALDH)2, an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts, and that an activator of ALDH2 reduced I/R injury in males but had no significant effect in females. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked the protection and the increased phosphorylation of ALDH2 in females, but had no effect in males. Furthermore, we found an increase in phosphorylation of -ketoglutarate dehydrogenase ( KGDH) in female hearts. KGDH is a major source of ROS generation particularly with a high NADH/NAD ratio which occurs during I/R. We found decreased ROS generation in permeabilized female mitochondria given KGDH substrates and NADH, suggesting that increased phosphorylation of KGDH might reduce ROS generation by KGDH. In support of this hypothesis, we found that protein kinase C–dependent phosphorylation of purified KGDH reduced ROS generation. Additionally, myocytes from female hearts had less ROS generation following I/R than males and addition of wortmannin increased ROS generation in females to the same levels as in males. Conclusions: These data suggest that posttranslational modifications can modify ROS handling and play an important role in female cardioprotection. (Circ Res. 2010;106:1681-1691.)
منابع مشابه
Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females.
RATIONALE Although premenopausal females have a lower risk for cardiovascular disease, the mechanism(s) are poorly understood. OBJECTIVE We tested the hypothesis that cardioprotection in females is mediated by altered mitochondrial protein levels and/or posttranslational modifications. METHODS AND RESULTS Using both an in vivo and an isolated heart model of ischemia and reperfusion (I/R), w...
متن کاملReactive Oxygen Species and p38MAPK Have a Role in the Smad2 Linker Region Phosphorylation Induced by TGF-β
Background: Transforming growth factor-β (TGF-β) in addition to the C-terminal region can phosphorylate receptor-regulated Smads (R-Smads) in their linker region. The aim of the present study was to evaluate the role of signaling mediators such as NAD(P)H oxidases (reactive oxygen species [ROS] generators), ROS, and ROS-sensitive p38 mitogen-activated protein kinase (p38MAPK) in this signaling ...
متن کاملCisplatin cytotoxicity is dependent on mitochondrial respiration in Saccharomyces cerevisiae
Objective(s): To understand the role of mitochondrial respiration in cisplatin sensitivity, we have employed wild-type and mitochondrial DNA depleted Rho0 yeast cells. Materials and Methods: Wild type and Rho0 yeast cultured in fermentable and non-fermentable sugar containing media, were studied for their sensitivity against cisplatin by monitoring growth curves, oxygen consumption, pH changes ...
متن کاملمروری بر نقش محافظتی ترکیبات پلی فنلی (رسوراترول، کوئرسیتین و کورکومین) بر عملکرد میتوکندری قلب
Mitochondria plays a major role in maintaining homeostasis of heart cells. Mitochondria produce ATP and is the main intracellular source of reactive oxygen species (ROS) which can cause oxidative damage. Free oxygen radicals and oxidative damage are associated with cardiovascular pathology. Antioxidant defense can play an essential role in preventing oxidative damage by controlling free oxygen ...
متن کاملAntioxidant Enzymes and Acute Phase Proteins Correlate with Marker of Lipid Peroxide in Adult Nigerian Sickle Cell Disease Patients
Objective(s) Sickle cell disease is a genetic disorder characterized by chronic haemolytic anaemia. Haemoglobin S containing red blood cells may be susceptible to oxidative stress due to imbalance between production of reactive oxygen species and the countering effect of the various antioxidants present in the body. Materials and Methods We evaluated some antioxidant enzymes which include gl...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2010