Christian Graesser, Nikita Panyam, Xiaofeng Qian, Tan An Dang, Benedikt Niedermeier, Michael Winkler, Johannes Riechel, M Amin Sharifi, Christin Noecker, Carla Abrahamian, Alexander Dietrich, Hendrik B Sager, Heribert Schunkert, Ling Li, Thorsten Kessler
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引用次数: 0
Abstract
The transient receptor potential cation channel subfamily member 6 (TRPC6) represents an emerging druggable target with a broad therapeutic spectrum. TRPC6 Inhibitors are currently investigated for focal segmental glomerulosclerosis (FSGS), acute respiratory distress syndrome due to COVID-19, and pulmonary hypertension. In the cardiovascular system, there is evidence that TRPC6 is critically involved in the development of cardiac hypertrophy, arrhythmia susceptibility and risk of restenosis after coronary stent implantation. However, data on systemic effects of TRPC6 modulation remain scarce. To assess the phenotypic consequences of inhibiting TRPC6 in different organ systems, we explored public databases to identify single nucleotide polymorphisms (SNPs) that are associated with TRPC6 expression in different tissues. A phenome-wide association study was then performed in 475,739 individuals of UK Biobank to associate genetically-mediated reduced TRPC6 expression with 64 phenotypes in nine organ/disease categories. Lower TRPC6 expression was nominally associated with reduced risk of anxiety, heart failure, and stroke, as well as an increased risk of venous thromboembolism, hypertension, appendicitis and liver cirrhosis. After correction for multiple testing, lower TRPC6 expression remained significantly associated with reduced risk of coronary artery disease and atrial fibrillation. Notably, no deleterious phenotypes were observed, suggesting a favorable profile of systemic TRPC6 inhibition. While these findings indicate potential therapeutic benefits, nominally associated phenotypes, however, mandate careful clinical investigation and provide a basis for further experimental exploration.
期刊介绍:
Journal of Cardiovascular Pharmacology is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. The Journal encourages submission in all aspects of cardiovascular pharmacology/medicine including, but not limited to: stroke, kidney disease, lipid disorders, diabetes, systemic and pulmonary hypertension, cancer angiogenesis, neural and hormonal control of the circulation, sepsis, neurodegenerative diseases with a vascular component, cardiac and vascular remodeling, heart failure, angina, anticoagulants/antiplatelet agents, drugs/agents that affect vascular smooth muscle, and arrhythmias.
Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, application of drugs to gain novel insights into physiology or pathological conditions, clinical results with new and established agents, and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases. Please note that JCVP does not publish work based on biological extracts of mixed and uncertain chemical composition or unknown concentration.