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Am J Physiol Heart Circ Physiol 274: H295-H307, 1998;
0363-6135/98 $5.00
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Vol. 274, Issue 1, H295-H307, January 1998

Changes in protein kinase C in early cardiomyopathy and in gracilis muscle in the BB/Wor diabetic rat

Thomas D. Giles, Jie Ouyang, E. Kenneth Kerut, Michael B. Given, Gayle Eileen Allen, Elizabeth F. McIlwain, and Stan S. Greenberg

Department of Medicine, Section of Cardiology, Cardiovascular Research Laboratories, and Department of Physiology, Alcohol Research Center, Louisiana State University Medical Center, New Orleans, Louisiana 70112

Hyperglycemia can upregulate protein kinase C (PKC), which may be an important mediator of the progression from normal heart and muscle function to diabetic myopathy in the myocardium and skeletal muscle in type 1 insulin-dependent diabetes mellitus (IDM). We evaluated this possibility during the early stage of IDM in BB/Wor diabetic (D) rats and age-matched BB/Wor diabetes-resistant (DR) rats. Interventricular septal thickness, E wave peak velocity of tricuspid inflow (both minimum and maximum), and left ventricular (LV) weight index were increased, and the rate of change in LV pressure (LV dP/dt) decreased in D rats subjected to M-mode and two-dimensional echocardiography and hemodynamic recording of heart rate, LV pressure (LVP), +LV dP/dt, -LV dP/dt, and LV end-diastolic pressure (LVEDP) in vivo and in vitro 41 days after the onset of hyperglycemia. Whole ventricle basal PKC activity was increased by 44.4 and 18.4% in the particulate and soluble fractions, respectively, from D rats compared with that from DR rats using r-32P phosphorylation of appropriate peptide substrates. When measured by Western blot gel densitometry, particulate PKC-alpha and PKC-delta content increased by 89 and 24%, respectively, but soluble PKC-beta and soluble and particulate PKC-epsilon were unchanged compared with that of DR rats. Similarly, gracilis muscle PKC activity and PKC-alpha and PKC-delta were elevated in the gracilis muscle, whereas that of the circulating neutrophil did not differ between the D and DR rats. Thus, in vivo, the early diabetic cardiomyopathy of the D rat is characterized by a restrictive LV with increased septal thickness and is associated with elevated PKC activity and increased amounts of myocardial particulate PKC-alpha and PKC-delta , which are also seen in the skeletal muscle. We conclude that increased PKC isozymes may play a pivotal role during IDM in the development of diabetic cardiomyopathy and skeletal muscle myopathy.

echocardiography; genetic diabetes; Doppler flowmetry; protein kinase C isozymes; myocardial contractility


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