Altered smooth muscle intracellular calcium signaling mechanisms in metabolic syndrome induced coronary artery disease.

摘要

Metabolic syndrome is the co-occurrence of hypertension, dyslipidemia, glucose intolerance, insulin resistance, and central obesity, which together increase the risk of coronary artery disease (CAD). The emerging Ossabaw swine developed metabolic syndrome and advanced CAD when fed excess high fat/cholesterol diet whereas the commonly used Yucatan swine did not. Stents mechanically revascularize occluded arteries due to advanced CAD however, restenosis within the stent oftentimes occurs due to stent-induced injury. We found elevated atherosclerotic restenosis within the stent in Ossabaw swine vs. Yucatan. Importantly, atherosclerotic tissue within the stent is of highly cellular content in Ossabaw, which is associated with upregulation of adenosine A1 receptor. In vitro studies indicated a causal role of adenosine A1 receptor in coronary smooth muscle cell proliferation. Augmented intracellular Ca2+ signaling events are associated with coronary smooth muscle cell proliferation, a major contributor to CAD. Coronary smooth muscle cell Ca2+ signaling events were augmented in Ossabaw swine with advanced CAD. The sarco-endoplasmic Ca2+ ATPase (SERCA) protein serves to reduce intracellular Ca2+ by pumping Ca2+ out of the myoplasm into the sarcoplasmic reticulum (SR), while the transient potential receptor canonical 1 (TRPC1) channel allows Ca 2+ influx into the cell when the SR Ca2+ store is depleted. We found SERCA dysfunction mediates augmented intracellular Ca2+ signaling events. Furthermore, SERCA dysfunction and TRPC1-mediated Ca 2+ influx is highly associated with smooth muscle cell proliferation and CAD. Exercise training, widely regarded as being beneficial for cardiovascular health, decreased CAD and reduced the magnitude of coronary smooth muscle cell Ca2+ signaling events. We have made the novel finding that SERCA dysfunction and elevated TRPC1-mediated Ca2+ influx is observed in CAD induced by metabolic syndrome.