Decreased Sarcoplasmic Reticulum Activity and Contractility in Diabetic db/db Mouse Heart

Abstract

Although it is known that insulin-dependent (type 1) diabetes results in depressed contractile performance associated with diminished sarcoendoplasmic reticular Ca 2؉ -ATPase (SERCA2a) activity, findings in insulinresistant (type 2) diabetes suggest a less clear association. The db/db insulin-resistant mouse model exhibits decreased cardiac performance both in situ and in isolated ex vivo working hearts. In this study, contractile performance and calcium transients were measured in Langendorff-perfused hearts and isolated cardiac myocytes. Diabetic (db/db) mouse hearts demonstrated decreased rates of contraction, relaxation, and pressure development. Calcium transients from isolated myocytes revealed significantly lower diastolic and systolic levels of calcium in diabetic hearts. Furthermore, the decay rate of the calcium transient was significantly reduced in diabetic myocytes, suggesting a diminished capacity for cytosolic calcium removal not associated with a change in sodium-calcium exchanger activity. Calcium leakage from the sarcoplasmic reticulum (SR) measured using tetracaine was significantly increased in diabetic myocytes. Western blot analysis indicated only a small decrease in SERCA2a expression in diabetic mice, but a large increase in phospholamban expression. Expression of the ryanodine receptor did not differ between groups. In conclusion, the decreased contractile function observed in the db/db diabetic mouse model appears to be related to decreased calcium handling by the SR. Diabetes 53: [3201][3202][3203][3204][3205][3206][3207][3208] 2004 H eart disease is the leading cause of death among diabetic patients. It has been recognized for a number of years that diabetes can impair myocardial performance independent of coronary artery disease or hypertension (1,2). Type 2 (noninsulin-dependent) diabetes is the most prevalent form of this disease, resulting from a combination of insulin resistance (resulting in hyperinsulinemia) and ultimately a failure of pancreatic ␤-cells to maintain adequate insulin secretion to overcome resistance (3,4). The etiology of type 2 diabetes is complex, arising from a mixture of genetic and environmental factors. In contrast, type 1 (insulin-dependent) diabetes is characterized by decreased insulin secretion and is readily reversed by insulin replacement. Although a number of studies have examined the effect of type 1 diabetes on contractile function in the heart, fewer such studies have been performed in type 2 diabetic models.The db/db mouse model of type 2 diabetes was originally isolated from the C57BLK6 strain Ͼ30 years ago (5). Disease development in this strain follows a distinct pattern. Outwardly, the mice are indistinguishable from their nondiabetic littermates until soon after weaning, when they show an accelerated gain in body mass. Initially, insulin secretion increases to overcome insulin resistance in the periphery to prevent hyperglycemia. By age 8 -12 weeks, the maximum extent of hyperinsulinemia is attained; hyperglycemia then develops when the ...

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

“…In a recent study, Belke and colleagues found decreased rates of contraction, relaxation and pressure development in hyperleptinaemic Lepr/Lepr diabetic mouse hearts [44]. While cardiac mechanical findings and the slowed intracellular Ca 2+ decay in Lepr/Lepr mice are consistent with our present observation in Lep/Lep mice, Lepr/Lepr diabetic myocytes displayed significantly reduced resting and peak Ca 2+ levels [44], contrary to our finding in Lep/Lep myocytes. Decreased, increased and unchanged resting intracellular Ca 2+ levels have been seen in diabetes, insulin resistance and obesity [2,45].…”

“…Most obese or overweight individuals display enhanced rather than reduced plasma levels of leptin, contrary to the leptindeficient status in Lep/Lep obesity [4]. In a recent study, Belke and colleagues found decreased rates of contraction, relaxation and pressure development in hyperleptinaemic Lepr/Lepr diabetic mouse hearts [44]. While cardiac mechanical findings and the slowed intracellular Ca 2+ decay in Lepr/Lepr mice are consistent with our present observation in Lep/Lep mice, Lepr/Lepr diabetic myocytes displayed significantly reduced resting and peak Ca 2+ levels [44], contrary to our finding in Lep/Lep myocytes.…”

Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

“…150 This scenario is also seen in the vast vasculature of SMT and its huge parenchyma, with an accelerated degradation of kinins by reduced release of these peptides from the working tissue. 155,156 As SMT has twenty times more mass than all tissues combined and possesses the largest vascular network, dysfunctions in this tissue will negatively impact not only the regulation of adequate energy supply in the working tissue itself, [157][158][159] but will also compromise the control of BP and glucose homeostasis in the whole organism. It is therefore not surprising that a disruption of ACE activity by these risk factors is accompanied by an exaggerated BP response during a workload 160 and by impaired insulin sensitivity in the face of a glucose challenge 161,162 (table 1).…”

Rosiglitazone and Cardiovascular Risk – A Review

“…Due to the cardiac problems associated with rosiglitazone, and the links between hypertension, cardiac dysfunction, microvascular diabetic complications (Advani et al, 2004;Belke et al, 2004;Singh et al, 2005) (Shah et al, 2004). In a related development, Randriamboavonjy et al, (2008) also demonstrated that treatment of megakaryocytes and platelets with rosiglitazone upregulates SERCA2b.…”