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Aldehydic load and skeletal muscle dysfunction: an opportunity to treat peripheral artery disease


Peripheral arterial disease (PAD) affects over 200 million people worldwide, causing significant disability and death. Typically, PAD is due to atherosclerosis, with obstruction of the iliac, femoral, and/or infrapopliteal arteries, and consequent reduction of blood supply to the lower extremities. Most of medical interventions of PAD stemmed from a vascular disease perspective. Although such 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 demonstrates that PAD patients have a profound skeletal muscle mitochondrial dysfunction, which is presumably triggered by intermittent ischemia-reperfusion injury caused by walking. Driven by this new paradigm, we have proposed a novel therapeutic strategy to ameliorate the ongoing myopathy and mitochondrial injury in PAD through a better clearance of mitochondrial aldehydes generated during oxidative stress, such as the lipid peroxidation-derived 4-hydroxynonenal (4-HNE). We have previously reported (FAPESP JP1#2012/05765-2) that 4-HNE plays a critical role in the establishment and propagation of ischemia-reperfusion injury in heart. 4-HNE is a lipophilic reactive aldehyde that accumulates during ischemia and irreversibly forms protein adducts; therefore propagating tissue damage with a negative impact on contractility and mitochondrial bioenergetics. Since reactive 4-HNE impairs mitochondrial metabolism, we propose that accelerated removal of 4-HNE will reduce the burden of carbonyl stress during ischemia-reperfusion injury, thus reducing mitochondrial injury and skeletal muscle damage in PAD. 4-HNE is mainly metabolized by the mitochondrial aldehyde dehydrogenase 2 (ALDH2). Using high-throughout screening, our group identified a small allosteric activator of ALDH2, termed Alda-1. Alda-1 treatment reduces 4-HNE protein adducts, improves mitochondrial metabolism and protects intact ex vivo organs and whole organisms against ischemia-reperfusion injury.Here, we hypothesize that ALDH2 activation will increase the removal of reactive 4-HNE, preserve mitochondrial metabolism, and thereby enhance skeletal muscle viability, function and PAD outcome. From a clinical perspective, this hypothesis is relevant since 4-HNE protein adducts accumulate in skeletal muscle biopsies from PAD patients; therefore suggesting impaired aldehyde metabolism. However, its role in PAD pathophysiology is still unknown. It is noteworthy that about 560 million people carry a common ALDH2 deficient variant (E487K mutation or ALDH2*2), which results in reduced enzymatic activity and elevated susceptibility to aldehyde intoxication and risk for cardiovascular disease. We have ALDH2*2 knockin mice in the lab, which will be used to test the association between ALDH2 deficiency and PAD. Our main goal is to understand the role of skeletal muscle mitochondrial aldehyde metabolism in PAD and translate our findings into meaningful therapy. (AU)

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