Increased cholesterol in metabolic syndrome Ossabaw swine precedes store‐operated Ca2+ influx and the development of coronary artery disease

Abstract

Metabolic syndrome (MetS) clearly predicts coronary artery disease (CAD). Ca2+ influx through store‐operated channels (SOC) is associated with vascular smooth muscle cell proliferation, which is a key feature of CAD. HYPOTHESIS: Dyslipidemia is a key component of MetS that increases SOC and CAD in Ossabaw miniature swine with MetS. A long‐term, 28 wk study compared 3 groups: 1) healthy, lean fed chow fed (N=6); 2) excess kcal high fructose diet that elicits MetS (N=5) defined by obesity, glucose intolerance, hypertriglyceridemia, and hypertension; 3) excess kcal high fructose/fat/cholesterol diet that elicits dyslipidemic MetS (DMetS; N=4) defined as the same MetS characteristics, but with increased cholesterol. Intravascular ultrasound revealed elevated CAD only in long‐term DMetS group. Baseline Ca2+ levels and SOC in coronary artery cells were assessed using fura‐2 imaging before and after sarcoplasmic reticulum Ca2+−store depletion. Baseline Ca2+ levels were increased 63% and SOC increased 2.4‐fold in DMetS vs. MetS and lean groups. A short‐term DMetS group (N=3) showed similar dyslipidemia as the long‐term DMetS, increased SOC vs. lean pigs, but no increased baseline Ca2+ or CAD. CONCLUSIONS: Increased cholesterol is crucial for SOC and CAD induction. This is the first report of increased SOC preceding increased smooth muscle Ca2+ concentrations and CAD. Support: NIH RR013223, HL062552.