NOVEL FEATURES OF CARDIOMYOPATHY IN STREPTOZOTOCIN-INDUCED DIABETIC RATS
Heart failure is the leading cause of death among diabetic patients. Cardiomyopathy has been shown to be an important contributing factor in heart failure, independent of atherosclerosis, hypertension, and other complications of diabetes. However, it is unknown what type of cardiomyopathy diabetes produces and what cellular and molecular mechanisms underlie contractile dysfunction. The objectives of the present study are to determine: 1) the type of cardiomyopathy in streptozotocin-induced diabetic rats, and 2) the mechanism underlying contractile dysfunction. Twelve-week diabetic rats showed decreased left ventricular (LV) posterior wall thickness with unchanged LV end-diastolic dimension as determined by echocardiographic and histological studies. Membrane capacitance measured by patch-clamp was diminished indicating reduced size in diabetic rat myocytes. The morphometric measurement of diabetic cardiocytes also revealed decreased cell length and width. Decreased cell size was due to growth arrest and contributed to thinner walls in diabetic rat hearts. Hence, decreased wall thickness due to smaller myocytes with unaltered chamber size in diabetic rats is a novel feature of this model. Depressed systolic and diastolic functions were consistently manifested in intact animals, isolated hearts, and single myocytes of diabetic rats. In single myocytes, dysregulation of cytosolic free calcium concentration ([Ca ^2+ ] c ) was associated with contractile dysfunction as indicated by the similar changes in contraction and [Ca ^2+ ] c transient parameters. Sarcoplasmic reticulum (SR) and sarcolemmal Na ^+ /Ca ^2+ exchanger (NCX) activities in situ in single myocytes were reduced and L-type Ca ^2+ channel activity was unchanged. Quantitative immunoblots demonstrated elevated phospholamban (PLB) and depressed PLB phosphorylation. SR Ca ^2+ -ATPase (SERCA2), ryanodine receptor, NCX protein levels were decreased in diabetic rat hearts. Increased PLB and decreased NCX protein expression are novel findings in this model. Consistent with increased non-phosphorylated PLB and decreased SERCA2, the apparent affinity of SR Ca ^2+ pump for Ca ^2+ and the maximum velocity of Ca ^2+ uptake were depressed in diabetic rat cardiac homogenates. In conclusion, streptozotocin-induced type 1 diabetes in rats produces a novel cardiac phenotype of smaller myocytes and thinner ventricular walls. A novel pattern of SR and NCX protein expression underlies [Ca ^2+ ] c dysregulation and is the major factor that underlies contractile dysfunction in diabetic rats.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:diabetes cardiomyopathy cardiac myocytes cytosolic calcium phospholamban
Date of Publication:01/01/2001