Increased Cholesterol is Vital to Impairment of TRPV1 Channel‐Mediated Relaxation of Coronary Artery In Ossabaw Miniature Swine with Metabolic Syndrome

Abstract

TRPV1 channels are implicated in vascular regulation. Ossabaw swine fed excess high fat/cholesterol diet develop metabolic syndrome (MetS), however studies find high‐fructose diets elicit MetS without dyslipidemia. We tested the hypothesis that dyslipidemia is an important component for eliciting dysfunction of endothelial cell (EC) TRPV1 channels signaling. Coronary arteries were studied from male Ossabaw pigs fed standard chow (lean, n = 8) or excess kcal diets for 28 wk: fructose to induce MetS (n = 6) or high fat/cholesterol/fructose to induce MetS with added dyslipidemia (DMetS, n = 8), defined by increased LDL or total/HDL cholesterol. The TRPV1 channel agonist capsaicin, dose‐dependently relaxed coronary rings from lean pigs (EC50 = 0.12 ± 0.04 μM), which was attenuated in MetS pigs (EC50 = 10 ± 21 μM) and severely attenuated in DMetS pigs (EC50: ~ 1mM). Fura‐2 imaging revealed capsaicin generated calcium influx in healthy EC, which was attenuated in MetS and to a greater extent in DMetS. Coronary TRPV1 protein levels were decreased only in DMetS (lean~MetS>DMetS). Conclusions: Capsaicin‐induced relaxation of coronary conduit artery occurs via EC and TRPV1 channel signaling, which is disrupted in MetS and to a much greater extent in DMetS, suggesting lipids are important regulators of EC TRPV1‐mediated functions. Support: NIH RR013223, HL062552, T32 HL079995.