Over the last years, the pathophysiology of cardiovascular disease has been associated to the formation and accumulation of oxidative stress-mediated aldehydes, which are highly cardiotoxic and contribute to the onset and / or aggravation of cardiovascular diseases. Among the various aldehydes accumulated in the heart, 4-hydroxy-2-nonenal (4-HNE), originated from the oxidation of inner mitochondrial membrane phospholipids, are extremely harmful to the heart.Localized in the mitochondrial matrix, the aldehyde dehydrogenase 2 (ALDH2) is the main enzyme responsible for the elimination of 4-HNE. Recently, our collaborators at Stanford University demonstrated an inverse correlation between ALDH2 activity and the degree of myocardial infarction after ex vivo cardiac ischemia. In fact, pharmacological inhibition of ALDH2 results in accumulation of 4-HNE and increased myocardial damage (1). Interestingly, a small ALDH2 activator (Alda-1) developed by the group was able to minimize the harmful effects of ischemia. Recently, we demonstrated that Alda-1 also has a protective effect during in vivo cardiac ischemia (2). Thus, these results highlight ALDH2 as a key enzyme in maintaining the cardiac viability during ischemic insults, opening a new perspective for treating cardiovascular diseases.In the present proposal we intend to better understand the role of ALDH2 in a myocardial infarction-induced heart failure (HF) animal model in rats. We hypothesized that the inactivation of ALDH2 due to redox imbalance in HF will result in the accumulation of 4-HNE, Michaelis adduct formation and aggravation of cardiac dysfunction. We intend to characterize the profile of protein expression and activity of ALDH2, and the accumulation of adducts Michaelis, oxidized proteins and lipid peroxidation rate. In addition, we will evaluate in cardiac isolated mitochondria from Sham and HF animals the following: oxygen consumption, production of hydrogen peroxide, inner membrane potential and maximum calcium uptake. Finally, we will analyze cardiac function and left ventricular remodeling in these animals.Since our preliminary results demonstrate an inhibition of ALDH2 in HF animals, we plan to study the benefits of sustained treatment with Alda-1 on the parameters described above. Therefore, in this research project we aim to: 1) understand the role of ALDH2 in myocardial-induced HF and 2) study the effect of Alda-1 on cardiac function, structure, metabolism and redox balance.
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