Biphasic alterations in coronary smooth muscle Ca²⁺ regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome

Background and aims: Coronary artery disease (CAD) is progressive, classified by stages of severity. Alterations in Ca²⁺ regulation within coronary smooth muscle (CSM) cells in metabolic syndrome (MetS) have been observed, but there is a lack of data in relatively early (mild) and late (severe) stages of CAD. The current study examined alterations in CSM Ca²⁺ regulation at several time points during CAD progression. Methods: MetS was induced by feeding an excess calorie atherogenic diet for 6, 9, or 12 months and compared to age-matched lean controls. CAD was measured with intravascular ultrasound (IVUS). Intracellular Ca²⁺ was assessed with fura-2. Results: IVUS revealed that the extent of atherosclerotic CAD correlated with the duration on atherogenic diet. Fura-2 imaging of intracellular Ca²⁺ in CSM cells revealed heightened Ca²⁺ signaling at 9 months on diet, compared to 6 and 12 months, and to age-matched lean controls. Isolated coronary artery rings from swine fed for 9 months followed the same pattern, developing greater tension to depolarization, compared to 6 and 12 months (6 months = 1.8 ± 0.6 g, 9 months = 5.0 ± 1.0 g, 12 months = 0.7 ± 0.1 g). CSM in severe atherosclerotic plaques showed dampened Ca²⁺ regulation and decreased proliferation compared to CSM from the wall. Conclusions: These CSM Ca²⁺ regulation data from several time points in CAD progression and severity help to resolve the controversy regarding up-vs. down-regulation of CSM Ca²⁺ regulation in previous reports. These data are consistent with the hypothesis that alterations in sarcoplasmic reticulum Ca²⁺ contribute to progression of atherosclerotic CAD in MetS.