Role of aldehyde dehydrogenase 2 during peripheral arterial disease progression.

Author(s)

Márcio Augusto Campos Ribeiro

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2017-09-21

Examining board members

Julio Cesar Batista Ferreira; Gabriel Grizzo Cucato; Cláudia Lúcia de Moraes Forjaz; Anselmo Sigari Moriscot

• Advisor: Julio Cesar Batista Ferreira

Abstract

Peripheral arterial disease (PAD) is a multifactorial disease which mainly affects elderly reducing quality of life and increasing cardiovascular mortality. Among the functional limitations imposed by the disease, the progressive worsening of locomotor capacity arising from intermittent periods of ischemia and reperfusion, are related to reduced muscle oxidative capacity, excessive oxidative stress and consequent accumulation of reactive aldehydes in the affected leg. We recently demonstrated that lipid peroxidation induced-toxic aldehydes accumulation contributes to ischemic heart disease progression. Interestingly, oxidation of these aldehydes through aldehyde dehydrogenase 2 (ALDH2) activation is cardioprotective. Based on that, this work characterizes the role of ALDH2 during PAD progression. The PAD animal model presents decreased skeletal muscle ALDH2 enzyme activity associated with exercise intolerance, muscle atrophy, poor muscle contraction, skeletal muscle sarcomeric disruption and giant mitochondrial accumulation. After ALDH2 inhibitor treatment, cell culture submitted to hypoxia/reoxygenation stress showed no angiogenesis and mitochondrial dysfunction. Similar data was seen at animal model, where PAD mice treated with ALDH2 inhibitor shows mitochondrial dysfunction, greater atrophy and affected physical exercise response. Also, transgenic mice for ALDH2 (which has a reduced ALDH2 activity) submitted to PAD showed a smaller muscle contraction, compared to wild type PAD mice. Our data points to ALDH2 as an important therapeutic target to develop new therapy strategies to counteract PAD progression. (AU)

• FAPESP's process: 15/01759-6 - Aldehyde dehydrogenase 2 profile in peripheral artery disease progression
• Grantee: Márcio Augusto Campos Ribeiro
• Support Opportunities: Scholarships in Brazil - Master