Dysfunction of coronary smooth muscle Ca²⁺ regulation in the progression of metabolic syndrome and coronary artery disease in Ossabaw miniature swine

Abstract

Coronary smooth muscle (CSM) cell Ca2+ regulation was studied in the Ossabaw swine model of metabolic syndrome (MetS) and coronary artery disease (CAD). MetS was induced by excess calorie atherogenic diet for 9 or 12 months and compared to lean controls on normal diet. Isometric tension studies on isolated coronary arteries revealed that 9 months of MetS increased tension development to KCl depolarization vs. lean controls, whereas 12 months reduced tension vs. control. MetS increases CAD and CSM Ca2+ dysregulation. CSM were isolated enzymatically and digitally imaged with the fluorescent Ca2+ indicator fura‐2. There was no difference in basal Ca2+ levels between groups. We released sarcoplasmic reticulum (SR) Ca2+ stores with caffeine. The peak Ca2+ release was increased in 9 month and decreased in 12 month MetS vs. lean. This Ca2+ response largely represents the caffeine‐sensitive SR Ca2+ store capacity. After the SR store depletion, a sustained Ca2+ signal above basal levels remained in the 9 month MetS group, reflecting store‐operated Ca2+ entry and decreased Ca2+ extrusion ability. Intravascular ultrasound and micro‐computed tomography imaging showed greater atherosclerosis and extracellular calcification in 12 vs. 9 month MetS. Collectively, these data suggest that CSM undergo dedifferentiation from a contractile to an osteogenic phenotype with progressively increasing CAD. (NIH HL062552, HL092245)