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Contribution of aldehyde dehydrogenase 2 to heart failure development

Grant number: 12/05765-2
Support type:Research Grants - Young Investigators Grants
Duration: July 01, 2012 - December 31, 2015
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Julio Cesar Batista Ferreira
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo, SP, Brazil
Associated scholarship(s):15/04462-4 - Intracelullar PKCepsilon-ALDH2 axis as a key mechanism in exercise-mediated cardioprotection, BP.MS
14/15187-1 - Characterization of skeletal muscle satellite cells metabolism and redox balance: role of aldehydes as metabolic sensors, BP.DR
13/24321-0 - Prior exercise induces cardioprotection against ischemia-reperfusion injury: contribution of the intracellular axis PKCepsilon-ALDH2, BP.IC
12/19379-7 - Role of ALDH2*2 mutation in heart failure: therapeutic potential of Alda-1, BP.DR

Abstract

The pathophysiology of cardiovascular disease has established that excessive generation and accumulation of aldehydes resulting from oxidative stress are highly cardiotoxic and contribute to the onset and / or aggravation of cardiovascular diseases. Among aldehydes accumulated in the heart, 4-hydroxynonenal (4-HNE), originated from the oxidation of phospholipids present in the inner mitochondrial membrane, has great toxicity to the heart. This electrophilic aldehyde is capable of attacking nucleophilic amino acids and form adducts with proteins (Michaelis adducts), resulting in inactivation of target proteins and consequent cellular dysfunction. The aldehyde dehydrogenase 2 (ALDH2), localized in the mitochondrial matrix, is considered the major enzyme responsible for the elimination of 4-HNE. We have recently found an inverse correlation between ALDH2 activity and the degree of myocardial infarction after cardiac ischemia, where both genetic and pharmacological inhibition of ALDH2 enzyme results in accumulation of 4-HNE and increased myocardial injury. In attempting to assess the therapeutic potential of ALDH2 activation in cardiovascular diseases, we performed a high-throughput screening with 600,000 molecules and identified a small molecule capable of selectively activating ALDH2. This molecule, called Alda-1 was able to keep the ALDH2 enzyme in its active state during the process of cardiac ischemia-reperfusion, minimizing the deleterious effects to the heart. Thus, these results highlight ALDH2 as a key enzyme in the removal of 4-HNE and maintenance of viability during cardiac ischemia-reperfusion, opening a new perspective in the treatment of cardiovascular diseases. In the current proposal, we plan to expand the knowledge regarding the role of ALDH2 in heart failure (HF) development. We will use specific tools developed during my post-doctorate, including the dominant negative transgenic mice for ALDH2, and the small molecule Alda-1, to better understand the ALDH2 contribution to HF progression, as well as the therapeutic potential of Alda-1.HF is a clinical syndrome characterized by cardiac dysfunction associated with exercise intolerance, fluid retention and reduced longevity. The current knowledge regarding the pathophysiology of HF has established that in addition to hemodynamic disturbances and neurohumoral hyper activation, changes in mitochondrial metabolism and redox imbalance contribute to the development of the pathophysiology. Based on this premise, we hypothesized that the mitochondrial dysfunction-mediated ALDH2 inactivation results in the accumulation of 4-HNE, formation of Michaelis adducts, which causes cellular collapse and cardiac dysfunction (see objectives below).This study is interesting and valuable since a better understanding of the role of ALDH2 in HF may contribute for future therapies acting on key mechanisms involved in the pathophysiology of HF, such as the activator of ALDH2 (Alda -1). Moreover, this proposal will bring a new research input for the Department of Anatomy-ICB-USP, including the use of integrative physiology associated with the cellular and molecular biology. Finally, our proposal is deeply supported by outstanding scientists Dr. Daria Mochly-Rosen, Stanford University, CA, USA; Dr. Alicia Kowaltowski Juliana and Dr. Deborah Schechtman, Department of Biochemistry- Chemistry Institute-USP, and Dr. Patricia Chakur Brum, School of Physical Education and Sports-USP. (AU)

Articles published in Agência FAPESP about the research grant
Molecule reduces heart function impairment after myocardial infarction 
Molecule shows potential for fighting heart failure  
Physical exercise helps prevent the worsening of heart failure