Résumé
Cardiovascular disease is the leading cause of death in the diabetic population. However, molecular mechanisms underlying diabetic cardiomyopathy remain unclear. We analyzed Ca super(2+)-induced Ca super(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 super(2+)] sub(i)) transient decrease in cardiomyocytes within the whole heart, which was also found in isolated myocytes by confocal microscopy. Global [Ca super(2+)] sub(i) transients are constituted of individual Ca super(2+) sparks. Ca super(2+) sparks in db/db cardiomyocytes were less frequent than in +/+ myocytes, partly because of a depression in sarcoplasmic reticulum Ca super(2+) load but also because of a reduced expression of ryanodine receptor Ca super(2+) channels (RyRs), revealed by [ super(3)H]ryanodine binding assay. Ca super(2+) efflux through Na super(+)/Ca super(2+) exchanger was increased in db/db myocytes. Calcium current, I sub(Ca), triggers sarcoplasmic reticulum Ca super(2+) release and is also involved in sarcoplasmic reticulum Ca super(2+) refilling. Macroscopic I sub(Ca) was reduced in db/db cells, but single Ca super(2+) channel activity was similar, suggesting that diabetic myocytes express fewer functional Ca super(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 super(2+). As less Ca super(2+) enters the cell through I sub(Ca), less Ca super(2+) is released through RyRs.