Hyperglycemia induces defective Ca 2+ homeostasis in cardiomyocytes

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 312; no. 1; pp. H150 - H161
• Main Authors: Sorrentino, Andrea, Borghetti, Giulia, Zhou, Yu, Cannata, Antonio, Meo, Marianna, Signore, Sergio, Anversa, Piero, Leri, Annarosa, Goichberg, Polina, Qanud, Khaled, Jacobson, Jason T., Hintze, Thomas H., Rota, Marcello
• Format: Journal Article
• Language: English
• Published: 01.01.2017
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00737.2016

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 β-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 Ca 2+ transients before the appearance of LV systolic defects. Alterations in Ca 2+ transients involved enhanced spontaneous Ca 2+ releases from the sarcoplasmic reticulum (SR), reduced cytoplasmic Ca 2+ clearance, and declined SR Ca 2+ load. These defects have important consequences on myocyte contraction, relaxation, and mechanisms of rate adaptation. Collectively, our data indicate that hyperglycemia alters intracellular Ca 2+ 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 Ca 2+ handling is a critical component of the progressive deterioration of cardiac performance of the diabetic heart.