Aldehyde dehydrogenase 2, mitochondrial bioenergetics and peripheral artery diseas...
| Grant number: | 15/01759-6 |
| Support type: | Scholarships in Brazil - Master |
| Effective date (Start): | May 01, 2015 |
| Effective date (End): | August 31, 2017 |
| Field of knowledge: | Biological Sciences - Physiology |
| Cooperation agreement: | Coordination of Improvement of Higher Education Personnel (CAPES) |
| Principal Investigator: | Julio Cesar Batista Ferreira |
| Grantee: | Márcio Augusto Campos Ribeiro |
| Home Institution: | Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
| Associated scholarship(s): | 16/16539-4 - Aldehyde dehydrogenase 2, mitochondrial bioenergetics and peripheral artery disease: is there any causality?, BE.EP.MS |
Abstract Peripheral Arterial Disease (PAD) affects over 10 million Americans, causing significant disability and death. Typically, PAD is due to atherosclerosis, with obstruction of the iliac, femoral, and/or infrapopliteal arteries. These patients are at high risk for death from heart attack or stroke because of disseminated atherosclerosis. Medical treatment of PAD is designed to reduce mortality and to relieve symptoms. However, new therapies are needed to relieve symptoms. Our approach to developing a novel therapy for PAD is based upon accumulating evidence that these patients have a profound mitochondriopathy, which is presumably caused by bouts of ischemia-reperfusion (I-R) induced by walking that leads to oxidative injury to the mitochondria in the ischemic muscle. Driven by this new paradigm, we have developed a novel therapeutic strategy to ameliorate the ongoing mitochondrial injury in PAD. Mitochondrial aldehyde dehydrogenase type 2 (ALDH2), a key-detoxifying enzyme, metabolizes both aliphatic and aromatic aldehydes that accumulate during oxidative stress. ALDH2 activity correlates with protection from myocardial injury by ischemia. We recently demonstrated that allosteric activation of ALDH2 by Alda-1 significantly reduces myocardial injury during ischemia-reperfusion. We hypothesize that ALDH2 activation will increase the removal of reactive aldehydes in the ischemic limb. We further hypothesize that ALDH2 activation will enhance skeletal muscle viability and function. Since reactive aldehydes such as 4-HNE damage the mitochondria, we propose that accelerated removal of 4-HNE and other toxic aldehydes will reduce the burden of carbonyl stress and reactive oxygen species (ROS), thus reducing tissue damage. Therefore, our goal is to understand the role of mitochondriopathy in PAD and translate our findings into meaningful therapy. (AU) | |