Hyperglycemia Induces Defective Ca2+ Homeostasis in Cardiomyocytes
Diabetes and other metabolic conditions characterized by elevated blood glucose constitute important risk factors for cardiovascular disease. Hyperglycemia targets myocardial cells rendering ineffective mechanical properties of the heart, but cellular alterations dictating the progressive deterioration of cardiac function with metabolic disorders remain to be clarified. In the current study, we examined the effects of hyperglycemia on cardiac function and myocyte physiology by employing mice with high blood glucose induced by administration of streptozotocin, a compound toxic to insulin-producing beta-cells. We found that hyperglycemia initially delayed the electrical recovery of the heart, whereas cardiac function became defective only after ~2 mo with this condition and gradually worsened with time. Prolonged hyperglycemia was associated with increased chamber dilation, thinning of the left ventricle (LV), and myocyte loss. Cardiomyocytes from hyperglycemic mice exhibited defective Ca2+ transients before the appearance of LV systolic defects. Alterations in Ca2+ transients involved enhanced spontaneous Ca2+ releases from the sarcoplasmic reticulum (SR), reduced cytoplasmic Ca2+ clearance, and declined SR Ca2+ load. These defects have important consequences on myocyte contraction, relaxation, and mechanisms of rate adaptation. Collectively, our data indicate that hyperglycemia alters intracellular Ca2+ homeostasis in cardiomyocytes, hindering contractile activity and contributing to the manifestation of the diabetic cardiomyopathy. NEW & NOTEWORTHY: We have investigated the effects of hyperglycemia on cardiomyocyte physiology and ventricular function. Our results indicate that defective Ca2+ handling is a critical component of the progressive deterioration of cardiac performance of the diabetic heart.
Sorrentino, A., Borghetti, G., Zhou, Y., Cannata, A., Meo, M., Signore, S., Anversa, P., Leri, A., Goichberg, P., Qanud, K., Jacobson, J., Hintze, T., & Rota, M. (2017). Hyperglycemia Induces Defective Ca2+ Homeostasis in Cardiomyocytes. American Journal of Physiology.Heart and Circulatory Physiology, 312 (1), H150-H161. https://doi.org/10.1152/ajpheart.00737.2016