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Therapeutic potential of the aldehyde dehydrogenase 2 activation in a model of aortic coarctation-induced pressure overload: role of ALDH2*2 mutation

Grant number: 13/11315-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2013
Effective date (End): September 30, 2016
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Cintia Bagne Ueta
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

We have recently demonstrated that aldehydic load contributes to the establishment/progression of myocardial infarction. Accumulation of 4-hydroxinonenal (4-HNE), a short and stable aldehyde generated during lipid peroxidation, results in protein-target inactivation and cardiac dysfunction. Aldehyde dehydrogenase 2 (ALDH2) plays a key role in metabolizing 4-HNE. Either pharmacological or genetic inhibition of ALDH2 results in 4-HNE accumulation and severe myocardial injury. Nearly 14% of the world's population have an ALDH2 single point mutation (ALDH2*2) that results in a drastic inhibition of its enzymatic activity. The aim of this study is to evaluate if transgenic mutant mice carrying the single point mutation ALDH2*2 are more susceptible to myocardial injury during aortic banding-induced cardiac pressure overload and the progression of heart failure. The hypothesis is that genetic ALDH2*2 inactivation increases cardiac 4-HNE levels and aggravates ventricular dysfunction due to cardiac pressure overload. To better understand the role of ALDH2 in our experimental model, we intend to characterize ventricular function and morphology as well as cardiac ALDH2 protein expression and activity profile in WT and mutant ALDH2*2 mice during cardiac pressure overload (3wks and 6wks after aortic banding surgery). In addition, we will measure cardiac aldehydic load, accumulation of Michaelis adducts, protein carbonyls and lipid peroxidation. Considering that aldehydic load impairs cellular metabolism and contractility, we will also characterize cardiac mitochondrial bioenergetics, calcium transient and contractility properties in isolated adult cardiomyocytes. Finally, we will test the efficacy of a long-term treatment with Alda-1 (a selective ALDH2 activator) in preserving cardiac contractility and metabolic properties upon cardiac pressure overload in WT and ALDH2*2 mice. Thus, the aims of the current proposal are: 1) to understand the role of ALDH2*2 mutation during the progression of cardiac overload-induced heart failure in mice and 2) to study the possible effect of Alda-1 in re-establishing ALDH2 activity in ALDH2*2 mice, as well as its consequences to cardiac function, structure, mitochondrial metabolism and cardiomyocyte contractility.

Articles published in Agência FAPESP about the scholarship:
Research in Brazil shows how a moderate dose of alcohol protects the heart 

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)
UETA, CINTIA BAGNE; CAMPOS, JULIANE CRUZ; PRESTES E ALBUQUERQUE, RUDA; LIMA, VANESSA MORAIS; DISATNIK, MARIE-HELENE; SANCHEZ, ANGELICA BIANCHINI; CHEN, CHE-HONG; GENNARI DE MEDEIROS, MARISA HELENA; YANG, WENJIN; MOCHLY-ROSEN, DARIA; BATISTA FERREIRA, JULIO CESAR. Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2. Cardiovascular Research, v. 114, n. 7, p. 1006-1015, JUN 1 2018. Web of Science Citations: 3.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.