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Chronic Alcohol Consumption Amplifies Intramuscular Oxidative Stress And Mitochondriopathy In Patients With Peripheral Artery Disease
Abstract   Peer reviewed

Chronic Alcohol Consumption Amplifies Intramuscular Oxidative Stress And Mitochondriopathy In Patients With Peripheral Artery Disease

Emma Fletcher, Dimitrios Miserlis, Evlampia Papoutsi, Iraklis Pipinos and Panagiotis Koutakis
Arteriosclerosis, thrombosis, and vascular biology, Vol.45(Supplement 1)
American Heart Association's Vascular Discovery: From Genes to Medicine (Baltimore, Maryland, USA, 04/22/2025–04/25/2025)
06/23/2025
DOI: https://doi.org/10.1161/atv.45.suppl_1.Th0081
Web of Science ID: WOS:001517434300115

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Abstract

Alcohol abuse and peripheral artery disease (PAD) are independent contributors to skeletal muscle damage; both characterized by mitochondriopathy. We recently showed that muscle structural damage is exacerbated in PAD patients with a history of heavy alcohol use, however, potential underlying mechanisms remain unexplored. Methods: We compared key markers of oxidative stress and mitochondrial electron transport chain (ETC) abundance in gastrocnemius muscle biopsies from PAD patients with heavy alcohol use (>14 or > 7 drinks/week, for males and females, respectively, n = 7) with PAD patients (n = 6) and non-PAD controls (n = 5) consuming moderate to low or no alcohol. The intramuscular content of alcohol dehydrogenase 1B (ADH1B), responsible for alcohol catabolism to reactive aldehydes, and aldehyde dehydrogenase 2 (ALDH2), which subsequently degrades toxic aldehydes, were also assessed. Results: Irrespective of drinking status, muscle oxidative stress (4-hydroxynonenol (4-HNE) and protein carbonyls) was significantly greater in PAD patients compared to non-PAD controls (P < .01). Mitochondrial ETC Complex I (CI) protein was also reduced in PAD muscle (P = .0008). Nevertheless, 4-HNE accumulation (P = .0002) and the extent of ETC CI loss (P = .0373) was significantly greater in heavy-drinking PAD (PAD-HD) patients compared to low to moderate drinkers (PAD-LD). The loss of ETC components was also more extensive in PAD-HD muscle and included reductions in all five complexes (P < .05). When the alcohol-metabolizing enzymes were assessed, PAD-HD muscle only showed a significant increase in ADH1B compared to control (P = .0314) and PAD-LD muscle (P = .0423). Interestingly, ALDH2 was unaltered in PAD-HD patients (P = .7777). but was significantly increased in PAD-LD compared to controls (P = .0041) and PAD-HD (P = .0087). Conclusions: Although traditionally known for regulating the breakdown of alcohol-derived toxic metabolites, ALDH2 also plays a key role in the removal of other reactive aldehydes, including those generated consequent to mitochondrial oxidative stress, such as 4-HNE and protein carbonyls. Considering ALDH2 was higher, and 4-HNE and ETC complex loss was lower in PAD-LD patients, an alcohol-derived dysfunction in ALDH2 may account for why intramuscular oxidative stress and mitochondriopathy was more extensive in PAD patients with heavy alcohol use. Thus, ALDH2 could be a promising therapeutic target to mediate oxidative stress in PAD patients.

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