Advanced search
Start date
Betweenand

Contribution of aldehyde dehydrogenase 2 to heart failure development

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 Newsletter about the research grant:
Articles published in other media outlets (0 total):
More itemsLess items
VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)

Scientific publications (15)
(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)
CHEN, CHE-HONG; BATISTA FERREIRA, JULIO CESAR; GROSS, ERIC R.; MOCHLY-ROSEN, DARIA. TARGETING ALDEHYDE DEHYDROGENASE 2: NEW THERAPEUTIC OPPORTUNITIES. Physiological Reviews, v. 94, n. 1, p. 1-34, . (12/05765-2)
DISATNIK, MARIE-HELENE; FERREIRA, JULIO C. B.; CAMPOS, JULIANE CRUZ; GOMES, KATIA SAMPAIO; DOURADO, PAULO M. M.; QI, XIN; MOCHLY-ROSEN, DARIA. Acute Inhibition of Excessive Mitochondrial Fission After Myocardial Infarction Prevents Long-term Cardiac Dysfunction. JOURNAL OF THE AMERICAN HEART ASSOCIATION, v. 2, n. 5, . (12/05765-2)
KIYUNA, LIGIA AKEMI; PRESTES E ALBUQUERQUE, RUDA; CHEN, CHE-HONG; MOCHLY-ROSEN, DARIA; BATISTA FERREIRA, JULIO CESAR. Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities. Free Radical Biology and Medicine, v. 129, p. 155-168, . (16/00900-0, 13/07937-8, 17/16694-2, 12/05765-2, 15/20783-5, 17/14426-0, 15/22814-5)
CAMPOS, JULIANE C.; QUELICONI, BRUNO B.; DOURADO, PAULO M. M.; CUNHA, TELMA F.; ZAMBELLI, VANESSA O.; BECHARA, LUIZ R. G.; KOWALTOWSKI, ALICIA J.; BRUM, PATRICIA C.; MOCHLY-ROSEN, DARIA; FERREIRA, JULIO C. B.. Exercise Training Restores Cardiac Protein Quality Control in Heart Failure. PLoS One, v. 7, n. 12, . (12/05765-2, 10/00028-4, 09/12349-2, 09/18546-4)
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; et al. Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2. Cardiovascular Research, v. 114, n. 7, p. 1006-1015, . (12/05765-2, 13/07937-8, 13/11315-2, 15/20783-5)
FERREIRA, JULIO C. B.; CAMPOS, JULIANE C.; QVIT, NIR; QI, XIN; BOZI, LUIZ H. M.; BECHARA, LUIZ R. G.; LIMA, VANESSA M.; QUELICONI, BRUNO B.; DISATNIK, MARIE-HELENE; DOURADO, PAULO M. M.; et al. A selective inhibitor of mitofusin 1-beta IIPKC association improves heart failure outcome in rats. NATURE COMMUNICATIONS, v. 10, . (10/00028-4, 15/22814-5, 17/16694-2, 17/11142-1, 12/05765-2, 10/51906-1, 17/16540-5, 09/12349-2, 16/01633-5, 16/09611-0, 15/20783-5)
CAMPOS, JULIANE CRUZ; FERNANDES, TIAGO; GRASSMANN BECHARA, LUIZ ROBERTO; DA PAIXAO, NATHALIE ALVES; BRUM, PATRICIA CHAKUR; DE OLIVEIRA, EDILAMAR MENEZES; BATISTA FERREIRA, JULIO CESAR. Increased Clearance of Reactive Aldehydes and Damaged Proteins in Hypertension-Induced Compensated Cardiac Hypertrophy: Impact of Exercise Training. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, . (12/05765-2, 06/56321-6)
GOMES, KATIA M. S.; CAMPOS, JULIANE C.; BECHARA, LUIZ R. G.; QUELICONI, BRUNO; LIMA, VANESSA M.; DISATNIK, MARIE-HELENE; MAGNO, PAULO; CHEN, CHE-HONG; BRUM, PATRICIA C.; KOWALTOWSKI, ALICIA J.; et al. Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling. Cardiovascular Research, v. 103, n. 4, p. 498-508, . (12/05765-2)
CAMPOS, JULIANE C.; GOMES, KATIA M. S.; FERREIRA, JULIO C. B.. Impact of exercise training on redox signaling in cardiovascular diseases. Food and Chemical Toxicology, v. 62, p. 107-119, . (12/05765-2, 12/14416-1)
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, . (12/14416-1, 12/19379-7, 16/01633-5, 12/05765-2, 15/20783-5)
UETA, CINTIA B.; GOMES, KATIA S.; RIBEIRO, MARCIO A.; MOCHLY-ROSEN, DANIA; FERREIRA, JULIO C. B.. Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities. PHARMACOLOGICAL RESEARCH, v. 115, p. 96-106, . (15/01759-6, 14/15187-1, 13/24321-0, 12/05765-2, 15/20783-5)
GOMES, KATIA M. S.; BECHARA, LUIZ R. G.; LIMA, VANESSA M.; RIBEIRO, MARCIO A. C.; CAMPOS, JULIANE C.; DOURADO, PAULO M.; KOWALTOWSKI, ALICIA J.; MOCHLY-ROSEN, DARIA; FERREIRA, JULIO C. B.. Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: Benefits of Alda-1. INTERNATIONAL JOURNAL OF CARDIOLOGY, v. 179, p. 129-138, . (12/05765-2, 13/07937-8, 10/51906-1)
CAMPOS, JULIANE C.; QUELICONI, BRUNO B.; BOZI, LUIZ H. M.; BECHARA, LUIZ R. G.; DOURADO, PAULO M. M.; ANDRES, ALLEN M.; JANNIG, PAULO R.; GOMES, KATIA M. S.; ZAMBELLI, VANESSA O.; ROCHA-RESENDE, CIBELE; et al. Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure. AUTOPHAGY, v. 13, n. 8, p. 1304-1317, . (10/51906-1, 10/00028-4, 09/12349-2, 16/01633-5, 12/05765-2, 15/20783-5)
CUNHA, TELMA F.; BECHARA, LUIZ R. G.; BACURAU, ALINE V. N.; JANNIG, PAULO R.; VOLTARELLI, VANESSA A.; DOURADO, PAULO M.; VASCONCELOS, ANDREA R.; SCAVONE, CRISTOFORO; FERREIRA, JULIO C. B.; BRUM, PATRICIA C.. Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats. Journal of Applied Physiology, v. 122, n. 4, p. 817-827, . (12/05765-2, 14/23703-0, 11/00728-9)
DISATNIK, MARIE-HELENE; HWANG, SUNHEE; FERREIRA, JULIO C. B.; MOCHLY-ROSEN, DARIA. New therapeutics to modulate mitochondrial dynamics and mitophagy in cardiac diseases. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 93, n. 3, p. 279-287, . (12/05765-2)

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