Cholesterol enrichment impairs Kir channels on resistance arteries and the Flow-induced Vasodilatation - Role of Aerobic Physical Training

• Grant number: 24/20798-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Health Sciences - Physiotherapy and Occupational Therapy
• Principal Investigator: Hugo Celso Dutra de Souza
• Grantee: Bruno Augusto Aguilar
• Supervisor: Shane Aaron Phillips
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of Illinois at Chicago (UIC), United States
• Associated to the scholarship: 22/02553-6 - Modulation role of aerobic physical training on hemodynamic and heart morphofunctional adaptations resulting from hypertension associated with ovarian hormone deprivation, BP.DD

Abstract

Introduction: Cardiovascular disease, primarily driven by endothelial dysfunction due to dyslipidemia, remains the leading cause of mortality globally. Endothelial inwardly-rectifying potassium (Kir2.1) channels play a crucial role in flow-induced vasodilation (FID) and nitric oxide (NO) production, both vital for vascular health. Research indicates that cholesterol enrichment suppresses Kir2.1 channels, impairing FID. Physical activity, known for its cholesterol-lowering effects, may potentially reverse these impairments. Hypothesis: We hypothesize that hypercholesterolemia suppresses Kir2.1 channel activity through cholesterol enrichment in endothelial cells, leading to impaired FID. Further, aerobic exercise training will mitigate this suppression, restoring Kir2.1 function and enhancing endothelial health. Objectives: We aim to investigate the impact of hypercholesterolemia on Kir2.1 activity and FID in human subcutaneous resistance arteries and, in addition, to assess the role of aerobic exercise training in reducing endothelial cholesterol and restoring Kir2.1 channel function. Methodology: The study will recruit hypercholesterolemic patients to assess endothelial membrane cholesterol, Kir2.1 expression, and FID. Participants will undergo a control period followed by a 4-week aerobic training program, with assessments conducted pre-and post-training. We will measure endothelial lipid packing, cholesterol content, and Kir2.1 function using electrophysiology, imaging, and molecular analyses.