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Aldehyde dehydrogenase 2, mitochondrial bioenergetics and peripheral artery disease: is there any causality?

Grant number: 16/16539-4
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): October 20, 2016
Effective date (End): April 19, 2017
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Márcio Augusto Campos Ribeiro
Supervisor abroad: Peter Darrell Neufer
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo, SP, Brazil
Local de pesquisa : East Carolina University (ECU), United States  
Associated to the scholarship:15/01759-6 - Aldehyde dehydrogenase 2 profile in peripheral artery disease progression, BP.MS

Abstract

Peripheral artery disease (PAD) is a multifactorial disease initially triggered by reduced blood supply to the lower extremities due to atherosclerotic obstructions. It is considered a major public health problem worldwide, affecting over 200 million people. Management of PAD includes smoking cessation, exercise, statin therapy, antiplatelet therapy, antihypertensive therapy and surgical intervention. Although these pharmacological and non-pharmacological interventions usually increase blood flow to the ischemic limb, morbidity and mortality associated with PAD continue to increase. This scenario raises new fundamental questions regarding the contribution of intrinsic metabolic changes in the distal affected limb to the progression of PAD. Recent evidence suggests that disruption of mitochondrial homeostasis triggered by intermittent ischemia-reperfusion injury in the affected limb is associated with increased morbidity in individuals with PAD. Indeed, individuals with PAD have a profound mitochondriopathy associated with accumulation of reactive molecules. Our preliminary results (see proposal #2015/01759-6 submitted to FAPESP) suggest that excessive accumulation endogenously generated toxic aldehydes [by-products of oxidative stress] contributes to PAD progression. In fact, transgenic knock-in mice carrying a mutation in the mitochondrial aldehyde dehydrogenase 2 (ALDH2), which confers loss of aldehyde clearance, develop PAD faster than wild-type littermates. Moreover, selective activation of ALDH2 using Alda-1 protects rodents against PAD. In the current proposal, we plan to study the contribution of mitochondrial metabolism to this process since toxic aldehydes may covalently bind to mitochondrial proteins and affect energy production in the affected limb. (AU)