Effect of metabolic syndrome and aging on Ca2+ dysfunction in coronary smooth muscle and coronary artery disease severity in Ossabaw miniature swine

Abstract

BACKGROUND: Metabolic syndrome (MetS) and aging are prevalent risk factors for coronary artery disease (CAD) and contribute to the etiology of CAD, including dysregulation of Ca2+ handling mechanisms in coronary smooth muscle (CSM). The current study tested the hypothesis that CAD severity and CSM Ca2+ dysregulation were different in MetS-induced CAD compared to aging-induced CAD. METHODS: 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 Ca2+ ([Ca2+]i) was assessed with fura-2 imaging. RESULTS: CAD severity was similar between MetS young and lean old swine, with MetS old swine exhibiting the most severe CAD. Compared to CSM [Ca2+]i handling in lean young, the MetS young and lean old swine exhibited increased sarcoplasmic reticulum Ca2+ store release, increased Ca2+ influx through voltage-gated Ca2+ channels, and attenuated sarco-endoplasmic reticulum Ca2+ ATPase activity. MetS old and MetS young swine had similar Ca2+ dysregulation. CONCLUSIONS: Ca2+ dysregulation, mainly the SR Ca2+ store, in CSM is more pronounced in lean old swine, which is indicative of mild, proliferative CAD. MetS old and MetS young swine exhibit Ca2+ 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 Ca2+ handling dysfunction in CAD.