Metabolic syndrome inhibits store-operated Ca 2+ entry and calcium-induced calcium-release mechanism in coronary artery smooth muscle

• Published in: Biochemical pharmacology 2020-12, Vol.182, p.114222
• Main Authors: Climent, Belén, Santiago, Elvira, Sánchez, Ana, Muñoz-Picos, Mercedes, Pérez-Vizcaíno, Francisco, García-Sacristán, Albino, Rivera, Luis, Prieto, Dolores
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Coronary Vessels - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Muscle, Smooth, Vascular - metabolism; Obesity - genetics; Obesity - metabolism; Organ Culture Techniques; Rats; Rats, Zucker
• ISSN: 1873-2968
• DOI: 10.1016/j.bcp.2020.114222

Metabolic syndrome causes adverse effects on the coronary circulation including altered vascular responsiveness and the progression of coronary artery disease (CAD). However the underlying mechanisms linking obesity with CAD are intricated. Augmented vasoconstriction, mainly due to impaired Ca homeostasis in coronary vascular smooth muscle (VSM), is a critical factor for CAD. Increased calcium-induced calcium release (CICR) mechanism has been associated to pathophysiological conditions presenting persistent vasoconstriction while increased store operated calcium (SOC) entry appears to activate proliferation and migration in coronary vascular smooth muscle (VSM). We analyze here whether metabolic syndrome might alter SOC entry as well as CICR mechanism in coronary arteries, contributing thus to a defective Ca handling and therefore accelerating the progression of CAD. Measurements of intracellular Ca ([Ca ] ) and tension and of Ca channels protein expression were performed in coronary arteries (CA) from lean Zucker rats (LZR) and obese Zucker rats (OZR). SOC entry stimulated by emptying sarcoplasmic reticulum (SR) Ca store with cyclopiazonic acid (CPA) was decreased and associated to decreased STIM-1 and Orai1 protein expression in OZR CA. Further, CICR mechanism was blunted in these arteries but Ca entry through voltage-dependent L-type channels was preserved contributing to maintain depolarization-induced increases in [Ca ] and vasoconstriction in OZR CA. These results were associated to increased expression of voltage-operated L-type Ca channel alpha 1C subunit (Ca 1.2) but unaltered ryanodine receptor (RyR) and sarcoendoplasmic reticulum Ca -ATPase (SERCA) pump protein content in OZR CA. The present manuscript provides evidence of impaired Ca handling mechanisms in coronary arteries in metabolic syndrome where a decrease in both SOC entry and CICR mechanism but preserved vasoconstriction are reported in coronary arteries from obese Zucker rats. Remarkably, OZR CA VSM at this state of metabolic syndrome seemed to have developed a compensation mechanism for impaired CICR by overexpressing Ca 1.2 channels.