Coronary Vascular Effects of Leptin and Calpastatin in Lean vs. Obese Hearts

Abstract

Recent evidence suggests a role for leptin and calpastatin in the pathogenesis of obesity‐induced coronary vascular dysfunction. However, how these factors affect coronary smooth muscle reactivity in lean vs. obese hearts is not well defined. Coronary arteries from lean and obese Ossabaw swine were isolated, cleaned of all surrounding adipose tissue, and incubated with or without leptin (3 – 30 ng/mL) or calpastatin (10 μM) for 30 min. Arteries were then pre‐constricted with the thromboxane mimetic U46619 (1μM). In untreated arteries, vasodilation to adenosine (0.01 – 30 μM) was decreased ~25% in obese compared to lean arteries. Administration of leptin dose‐dependently reduced vasodilation to adenosine, with the 30 ng/mL concentration attenuating dilation ~25% in both lean and obese arteries. In contrast, the presence of calpastatin impaired responses to adenosine (10 μM) in lean (~26%), but not obese arteries. In additional studies, coronary arteries from lean swine were cultured at 37oC in the presence/absence of leptin (30 ng/mL) or calpastatin (10 μM) for 3 days and subsequently subjected to functional isometric tension studies. Relative to untreated cultured arteries, incubation with leptin augmented active tension development to KCl‐induced depolarization (30 mM) and diminished vasodilation in response to adenosine (10 μM). Incubation with calpastatin modestly reduced vasodilation to adenosine but did not influence active tension development to KCl. These findings indicate that leptin and calpastatin differentially influence vascular function and suggest that these factors could contribute to the augmented contractile, impaired vasodilator phenotype of the obese coronary circulation.