Effect of metabolic syndrome and aging on Ca 2+ dysfunction in coronary smooth muscle and coronary artery disease severity in Ossabaw miniature swine

Metabolic syndrome (MetS) and aging are prevalent risk factors for coronary artery disease (CAD) and contribute to the etiology of CAD, including dysregulation of Ca handling mechanisms in coronary smooth muscle (CSM). The current study tested the hypothesis that CAD severity and CSM Ca dysregulation were different in MetS-induced CAD compared to aging-induced CAD. Young (2.5 ± 0.2 years) and old (8.8 ± 1.2 years) Ossabaw miniature swine were fed an atherogenic diet for 11 months to induce MetS and were compared to lean age-matched controls. The metabolic profile was confirmed by body weight, plasma cholesterol and triglycerides, and intravenous glucose tolerance test. CAD was measured with intravascular ultrasound and histology. Intracellular Ca ([Ca ] ) was assessed with fura-2 imaging. CAD severity was similar between MetS young and lean old swine, with MetS old swine exhibiting the most severe CAD. Compared to CSM [Ca ] handling in lean young, the MetS young and lean old swine exhibited increased sarcoplasmic reticulum Ca store release, increased Ca influx through voltage-gated Ca channels, and attenuated sarco-endoplasmic reticulum Ca ATPase activity. MetS old and MetS young swine had similar Ca dysregulation. Ca dysregulation, mainly the SR Ca store, in CSM is more pronounced in lean old swine, which is indicative of mild, proliferative CAD. MetS old and MetS young swine exhibit Ca dysfunction that is typical of late, severe disease. The more advanced, complex plaques in MetS old swine suggest that the "aging milieu" potentiates effects of Ca handling dysfunction in CAD.