Abstract 074: Endothelial Caveolin-1 Mediates The Effects Of Dietary Sodium On Cardiovascular And Metabolic Function

Hypertension and insulin resistance (IR) are often associated with endothelial dysfunction; however, the underpinnings of their association are not well understood. Caveolin-1 (cav1) is a transmembrane protein identified in many cell types including cardiovascular (CV) and adipose cells. Our recent findings in mice and humans consistently suggest a role of cav1 in IR, dyslipidemia, CV dysfunction and hypertension in response to sodium loading. While adipose cav1 has been established as a critical mediator of glucose and lipid homeostasis, the role of endothelial cav1 in cardiometabolic dysfunction , and its relationship with dietary sodium is unclear. To test whether the cav1 in the endothelium mediates the effect of dietary sodium on CV and metabolic function, we used the Cre- loxP technology to generate a novel, endothelium-specific cav1 KO mouse model (Ecav1 KO). Glucose tolerance, BP, fasting insulin, lipids and the state of circulating RAAS were measured in Ecav1 KO and WT mice studied on low- and high-sodium diets (0.03 vs 1.6% Na) for 7 days. Ecav1 KO and WT mice had similar BW, food and water intake and urinary output on either diet. Compared to the WT, Ecav1 KO animals had significantly higher fasting blood glucose levels on a LS diet (103±4 vs 87±3 mg/dl, p<0.01) but not on a HS diet. Ecav1 KO mice also had impaired glucose tolerance vs the WT, especially on a HS diet; however, the glucose intolerance was not as pronounced in the Ecav1 KO as in the full cav1 KO. There were no differences in fasting insulin or lipid levels between the genotypes. On a HS diet, Ecav1 KO vs WT mice had significantly higher SBP levels (117±2 vs 109±3 mmHg, p<0.05). In addition, they had significantly higher pulse pressure (38±2 vs 29±1 mmHg, p<0.01), heart rates (802±11 vs 725±12 bpm, p<0.01) and rate pressure products, consistent with increased arterial stiffness and myocardial workload. These changes could not be explained by differences in kidney function; however, aldosterone levels were increased in Ecav1 KO vs WT animals (74±11 vs 48±5 ng/dl) despite no changes in PRA. Our findings are consistent with a direct role of endothelial cav1 in the development of IR and CV dysfunction, and highlight the importance of endothelial function in cardiometabolic homeostasis.

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