Abstract 21413: Molecular Basis of Maternal Obesity Induced Fetal Cardiac Contractile Dysfunction

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One third of the women at reproductive age are overweight or obese in US. Epidemiological studies in humans and studies on animals have shown that obesity during pregnancy (i.e. maternal obesity, MO) increases incidences of cardiovascular diseases in offspring. Uterus environment is essential for fetal cardiac development and MO as a stress condition in uterus could program cardiovascular disease in prenatal and postnatal offspring. However, the mechanisms of the origin and development of MO-induced cardiovascular disease later in life remain unclear. For this purpose, we use sheep (sharing many similarities with human pregnancy) as a model to study the impact of MO on fetal heart contractile function. Previously, we have demonstrated that MO impaired fetal sheep cardiomyocyte contractility by reducing the peak shortening and velocity of shortening/relengthening and prolonged the time to peak shortening/relengthening. We also found that MO disrupted the calcium homeostasis in fetal cardiomyocytes by increasing intracellular Ca2+ level and inducing the calcium insensitivity in the cell. In current study, we found that MO increased the phosphorylation of protein kinase A (PKA) as well as the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), which further promoted phosphorylation level of ryanodine receptor type 2 (Ryr2) at Ser2808 and Ser2814 respectively. Expression level of FKBP12.6, a key protein interacting with Ryr2 for calcium releasing, was upregulated in MO fetal myocardium. On the other hand, MO reduced expression of myosin heavy chain in fetal myocardium. Moreover, the cardiac troponin T and troponin I expression level was upregulated in MO fetuses, whereas MO downregulated the expression of troponin C in fetal myocardium. Taken together, our findings suggest that increased CaMKII and PKA phosphorylation of Ryr2 plays a critical role in the development of MO-induced sarcoplasmic reticulum Ca2+ leak in fetal cardiomyocytes. Furthermore, our data indicate that the change in expression levels of myosin heavy chain and troponin C, I and T is the cause of calcium insensitivity and contractile dysfunction in MO fetal cardiomyocytes. Our studies have provided a fundamental molecular basis of MO programmed heart disease.

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