Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy

Abstract

The effects of insulin and thyroid hormone treatments on cardiac sarcoplasmic reticular function were investigated in chronic streptozotocin-induced diabetes in rats. ATP-dependent Ca2+ transport and Ca2+-stimulated ATPase activities were depressed significantly in microsomal samples from diabetic rats in comparison with control (P less than 0.05). This defect was seen at various times of incubation (1-20 min) and different concentrations of free Ca2+ (10(-7) to 10(-5) M Ca2+) and was accompanied by changes in the protein composition and phospholipid contents of the microsomal fraction. The defect in calcium transport in microsomal vesicles was not evident until 28 days after streptozotocin (65 mg/kg iv) injection, whereas increases in plasma glucose levels due to insulin-deficiency occurred within 3 days. All changes in function and composition of the sarcoplasmic reticulum were reversed by insulin administration to the diabetic rats. Although the plasma level of thyroid hormone was decreased in the diabetic rat, thyroid hormone treatment did not restore microsomal calcium transport in the diabetic animals. The results of this study provide some evidence that the depression in cardiac sarcoplasmic reticular calcium accumulation during diabetes is a consequence of insulin deficiency and associated chronic metabolic changes but the hypothyroid condition that accompanies experimental diabetes does not appear to play any role in this defect.

Ventricular relaxation of diabetic spontaneously hypertensive rat.

“…7 Proposed mechanisms include reductions in either the density or the activity of 2 1 ATPase, 8 ' 9 ' 18 alterations in membrane Values represent mean±SD obtained 8 weeks after initiation of diabetes or treatment. P m maximum left ventricular developed pressure (LVDP); Tp, time to P ,^ T n time from P,^, to minimum LVDP; LV-dP/dt, maximum rate of left ventricular pressure decline; SHR, spontaneously hypertensive rats; T 3 , triiodothyronine; I, protamine zinc insulin; WKY, Wistar-Kyoto rats.…”

“…lipid profiles, 8 -2829 and changes in the degree of membrane phosphorylation. 30 Until now, studies of this kind have been restricted to nonhypertensive, nonhypertrophic models.…”

“…Earlier studies had indicated that "physiological doses" of thyroid hormone (i.e., those that had been shown to be sufficient for replacement therapy of simple hypothyroidism) were only partially effective in restoring cardiac function of diabetic normotensive rats. 8 - 23 " 25 Interestingly, however, T 3 (10 Aig/kg b.i.d.) given for only the final 5 days of a 2-week period of diabetes, almost completely reversed the prolonged action potential duration in diabetic Wistar rat atria.…”

Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy

“…As a consequence, the SR calcium content declines, leading to a reduced systolic calcium release and therefore a weaker cardiac contraction (9,10). At the molecular level, the impairment of SR function was shown to be caused by a reduced activity of the SR calcium pump (SERCA2a), which induced diastolic relaxation by sequestering calcium from the cytoplasm (11). SERCA2a activity depends on the amount of SERCA2a protein and is further regulated by its inhibitory protein phospholamban.…”

Abnormal myocardial perfusion and contractile recruitment during exercise in type 1 diabetic patients

“…1,2 Several defects have been proposed to explain the pathogenesis of diabetic cardiomyopathy, including a reduced adrenoreceptor myocardial density, alterations in contractile proteins, impaired calcium cellular movements, and defective energy metabolism. [1][2][3][4][5] Several anatomical and functional abnormalities of the microcirculation were recognized in the human diabetic heart without obstructive coronary atherosclerosis or coexisting arterial hypertension. 6 Moreover, it has been shown that DM is associated with both reduced coronary flow reserve [7][8][9] and impaired endothelial-dependent epicardial coronary vasodilation.…”