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

Abstract

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.