Cardiovascular disease (CVD) is highly prevalent among the Native Hawaiian and Pacific Islanders (NHPIs). The exact reason(s) responsible for heightened CVD in NHPIs is unclear, and there is an urgent need for innovative therapeutic approaches. Autophagy is a conserved process that degrades and recycles damaged intracellular organelles to generate energy and maintain proteostasis. Our laboratory has shown that autophagy preserves endothelial cell (EC) and cardiac function in the context of aging. Sequestosome 1 (p62) is one of the proteins responsible for tethering damaged intracellular organelles into the autophagy pathway for lysosomal degradation. We will examine the impact of EC-specific p62 deletion on peripheral glucose homeostasis and cardiac function. P62 will be depleted from ECs of adult male and female mice (KO) using genetic procedures, and results will be compared to animals wherein EC p62 is intact (CON). Fourteen days after administering tamoxifen to both groups of mice: (i) body composition will be assessed via nuclear magnetic resonance; (ii) glucose disposal and insulin sensitivity will be measured in response to a glucose and insulin tolerance tests; (iii) and systolic and diastolic function will be assessed by echocardiography. Each test will be separated by 4 days. At tissue collection, the efficacy and specificity of EC p62 depletion will be evaluated by measuring p62 mRNA (qPCR) in carotid arterial ECs, and p62 protein (immunoblotting) expression in lung ECs. Our findings will reveal the impact of EC-specific p62 depletion on peripheral glucose metabolism, body composition, and cardiac function for the first time. This project is supported by: NIH RO1 HL141540 (JDS); AHA23PRE1025910 (SM); RUUTE Program (CG) and PIRIP (LG).