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