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Role of ALDH2*2 mutation in heart failure: therapeutic potential of Alda-1

Grant number: 12/19379-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2012
Effective date (End): September 30, 2016
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Vanessa Morais Lima
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/05765-2 - Contribution of aldehyde dehydrogenase 2 to heart failure development, AP.JP

Abstract

The knowledge about the physiopathology of cardiovascular diseases have established that the formation and accumulation of aldehydes of oxidative stress are extremely cardiotoxic and contribute to the onset and / or worsening of these diseases. Among the various aldehydes accumulated in the heart, the 4-hydroxy-2-nonenal (4-HNE), originating from the oxidation of phospholipids present in the inner mitochondrial membrane, is capable of attack nucleophilic amino acids to form adducts with proteins, resulting in inactivation of the target protein and subsequent cellular dysfunction.The main enzyme responsible for the elimination of 4-HNE is aldehyde dehydrogenase 2 (ALDH2) located in the mitochondrial matrix. Both pharmacological and genetic inhibition of ALDH2 gene results in the accumulation of HNE-4 and increased myocardial injury. Actually, it is estimated that 14% of the world population has a mutation of ALDH2 (ALDH2 * 2) which gives up to 95% loss in its enzymatic activity. In this research project we intend to evaluate whether mice that have the ALDH2 * 2 mutation are more susceptible to heart damage from myocardial infarction and progression of heart failure (HF).Heart failure is a clinical syndrome characterized by poor prognostic cardiac dysfunction associated with intolerance to exertion, fluid retention and reduced longevity. In recent years, our understanding of the physiopathology of HF established that addition of hemodynamic and neuro-hormonal disturbances associated with the syndrome, alterations in mitochondrial metabolism and redox imbalance consequent can impair cardiac function. Based on this premise, hypothesized that the inactivation of ALDH2 resulting from ALDH2 * 2 mutation exacerbate the accumulation of 4-HNE, the formation of adducts Michaelis and worsening of ventricular dysfunction due to myocardial infarction. Aiming to better understand the role of ALDH2 in HF, we intend to characterize the profile of protein expression and activity of ALDH2 in hearts of mice, wild and mutants with HF of ischemic etiology. Furthermore, we will evaluate the accumulation of adducts Michaelis, carbonyls protein and lipid peroxidation heart. Whereas the accumulation of adducts Michaelis can impair cellular metabolism, we will evaluate in mitochondria isolated of cardiac tissue of animals: oxygen consumption, the production of hydrogen peroxide, the potential of the inner membrane and the maximum uptake of calcium. Finally, it will be analyzed: left ventricular remodeling, cardiac function and contractility / transient calcium in cardiomyocytes isolated from these animals.Whereas previous results from our group demonstrated an inefficiency of ALDH2 in the removal of cytotoxic aldehydes in animals with HF, will be of great value to study the effect of sustained treatment with the selective activator of ALDH2, Alda-1 on the parameters described above in wild and mutant for ALDH2. The Alda-1 molecule, developed by our collaborators at Stanford University, CA, USA, is able to correct the loss of ALDH2 function caused by ALDH2 * 2 mutation. Therefore, in this research project we aim to: 1) understand the role of ALDH2 * 2 mutation in the progression of HF of ischemic etiology and 2) study the possible effect of Alda-1 on the inactivation of ALDH2 resulting from ALDH2 * 2 mutation, as well as its effect on cardiac structure and function, mitochondrial metabolism and redox balance. This study is interesting because the more detailed understanding of the role of the ALDH2 mutation in the progression of HF may contribute to the future use of therapies that act on the key mechanisms involved in the physiopathology of HF, as the activator of ALDH2, Alda-1.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAMPOS, JULIANE C.; BOZI, LUIZ H. M.; BECHARA, LUIZ R. G.; LIMA, VANESSA M.; FERREIRA, JULIO C. B. Mitochondrial Quality Control in Cardiac Diseases. FRONTIERS IN PHYSIOLOGY, v. 7, OCT 21 2016. Web of Science Citations: 15.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
LIMA, Vanessa Morais. Role of ALDH2*2 mutation in heart failure: therapeutic potencial of Alda-1.. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas São Paulo.

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