Year: 2025
Type: article
Abstract: ABSTRACT Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here we show that mice lacking SCoR2/Akr1a1 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2 -/- mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways—ketone body utilization, glycolysis, pentose phosphate shunt and polyol metabolism—to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target. Impact statement Mice lacking the denitrosylase enzyme SCoR2 demonstrate robust cardioprotection resulting from coordinate reprogramming of multiple metabolic pathways. GRAPHICAL ABSTRACT
Source: eLife
Authors: Zachary W. Grimmett, Rongli Zhang, Hua-Lin Zhou, Qiuying Chen, Dawson Miller, Zhaoxia Qian, Justin Lin, Riti Kalra, Steven S. Gross, Walter J. Koch, Richard T. Premont, Jonathan S. Stamler
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: American Heart Association, Case Western Reserve University, National Institutes of Health, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Metabolic remodeling of skeletal muscle in mitochondrial myopathies, G1573666252, G2373605226, G2573887198, Role of S-Nitrosylation on Beta-Adrenergic Signaling in Cardiac Injury and Repair, Medical Scientist Training Program, G3593636442, G4453228874, Gut Microbe-Derived Nitric Oxide As A Signal To Host: Role In Normal Physiology And In Disease, G5763760732, G7148773069, G7626856297, G7662419750, G8464692053, Scientific innovation for personalized severe asthma management, Restoration and Function of S-Nitrosothiol in Stored Blood, Metabolic Landscape and Mitochondrial ROS Balance in Brain Ischemia/Reperfusion, Novel Regulation of Renal Function by S-Nitrosylation
OpenAlex ID: W4408422261