Interaction between Age and Obesity on Cardiomyocyte Contractile Function: Role of Leptin and Stress Signaling

OBJECTIVES: This study was designed to evaluate the interaction between aging and obesity on cardiac contractile and intracellular Ca(2+) properties. METHODS: Cardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the leptin deficient ob/ob obese mice were treated with leptin (0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obesity models at young and older age were used for comparison. Cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), intracellular Ca(2+) levels and decay. O(2) (−) levels were measured by dihydroethidium fluorescence. RESULTS: Our results revealed reduced survival in ob/ob mice. Aging and obesity reduced PS, ± dL/dt, intracellular Ca(2+) rise, prolonged TR(90) and intracellular Ca(2+) decay, enhanced O(2) (−) production and p (47phox) expression without an additive effect of the two, with the exception of intracellular Ca(2+) rise. Western blot analysis exhibited reduced Ob-R expression and STAT-3 phosphorylation in both young and aging ob/ob mice, which was restored by leptin. Aging and obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK and pIκB. Low levels of leptin reconciled contractile, intracellular Ca(2+) and cell signaling defects as well as O(2) (−) production and p (47phox) upregulation in young but not aging ob/ob mice. High level of leptin (50 nM) compromised contractile and intracellular Ca(2+) response as well as O(2) (−) production and stress signaling in all groups. High fat diet-induced and db/db obesity displayed somewhat comparable aging-induced mechanical but not leptin response. CONCLUSIONS: Taken together, our data suggest that aging and obesity compromise cardiac contractile function possibly via phosphorylation of Akt, eNOS and stress signaling-associated O(2) (−) release.