Mechanisms of (Ca2+)i Transient Decrease in Cardiomyopathy of db/db Type 2 Diabetic Mice.

摘要

Cardiovascular disease is the leading cause of death in the diabetic population. However, molecular mechanisms underlying diabetic cardiomyopathy remain unclear. We analyzed Ca(2+)-induced Ca(2+) release and excitation-contraction coupling in db/db obese type 2 diabetic mice and their control littermates. Echocardiography showed a systolic dysfunction in db/db mice. Two-photon microscopy identified intracellular calcium concentration ([Ca(2+)](i)) transient decrease in cardiomyocytes within the whole heart, which was also found in isolated myocytes by confocal microscopy. Global [Ca(2+)](i) transients are constituted of individual Ca(2+) sparks. Ca(2+) sparks in db/db cardiomyocytes were less frequent than in +/+ myocytes, partly because of a depression in sarcoplasmic reticulum Ca(2+) load but also because of a reduced expression of ryanodine receptor Ca(2+) channels (RyRs), revealed by [(3)H]ryanodine binding assay. Ca(2+) efflux through Na(+)/Ca(2+) exchanger was increased in db/db myocytes. Calciumcurrent, I(Ca), triggers sarcoplasmic reticulum Ca(2+) release and is also involved in sarcoplasmic reticulum Ca(2+) refilling. Macroscopic I(Ca) was reduced in db/db cells, but single Ca(2+) channel activity was similar, suggesting that diabetic myocytes express fewer functional Ca(2+) channels, which was confirmed by Western blots. These results demonstrate that db/db mice show depressed cardiac function, at least in part, because of a general reduction in the membrane permeability to Ca(2+). As less Ca(2+) enters the cell through I(Ca), less Ca(2+) is released through RyRs.