Abstract
Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with diabetes are collectively called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed that could contribute to the development of diabetic cardiomyopathy and have been studied in various animal models of type 1 or type 2 diabetes. The current review focuses on the role of sodium (Na(+)) in diabetic cardiomyopathy and provides unique data on the linkage between Na(+) flux and energy metabolism, studied with non-invasive (23)Na, and (31)P-NMR spectroscopy, polarography, and mass spectroscopy. (23)Na NMR studies allow determination of the intracellular and extracellular Na(+) pools by splitting the total Na(+) peak into two resonances after the addition of a shift reagent to the perfusate. Using this technology, we found that intracellular Na(+) is approximately two times higher in diabetic cardiomyocytes than in control possibly due to combined changes in the activity of Na(+)-K(+) pump, Na(+)/H(+) exchanger 1 (NHE1) and Na(+)-glucose cotransporter. We hypothesized that the increase in Na(+) activates the mitochondrial membrane Na(+)/Ca(2+) exchanger, which leads to a loss of intramitochondrial Ca(2+), with a subsequent alteration in mitochondrial bioenergetics and function. Using isolated mitochondria, we showed that the addition of Na(+) (1-10 mM) led to a dose-dependent decrease in oxidative phosphorylation and that this effect was reversed by providing extramitochondrial Ca(2+) or by inhibiting the mitochondrial Na(+)/Ca(2+) exchanger with diltiazem. Similar experiments with (31)P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na(+) (3-30 mM) led to significantly decreased ATP levels and that this effect was stronger in diabetic rats. These data suggest that in diabetic cardiomyocytes, increased Na(+) leads to abnormalities in oxidative phosphorylation and a subsequent decrease in ATP levels. In support of these data, using (31)P-NMR, we showed that the baseline β-ATP and phosphocreatine (PCr) were lower in diabetic cardiomyocytes than in control, suggesting that diabetic cardiomyocytes have depressed bioenergetic function. Thus, both altered intracellular Na(+) levels and bioenergetics and their interactions may significantly contribute to the pathology of diabetic cardiomyopathy.