CHANGES IN PROTEIN-KINASE-C IN EARLY CARDIOMYOPATHY AND IN GRACILIS MUSCLE IN THE BB WOR DIABETIC RAT/

Hyperglycemia can upregulate protein kinase C (PKC), which may be an i mportant mediator of the progression from normal heart and muscle func tion to diabetic myopathy in the myocardium and skel- etal muscle in t ype 1 insulin-dependent diabetes mellitus (IDM). We evaluated this pos sibility during the early stage of IDM in BB/Wor diabetic (D) rats and age-matched BB/Wor diabetes-resistant (DR) rats. Interventricular sep tal thickness, E wave peak velocity of tricuspid inflow (both minimum and maximum), and left ventricular (LV) weight index were increased, a nd the rate of change in LV pressure (LV dP/dt) decreased in D rats su bjected 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 inc reased by 44.4 and 18.4% in the particulate and soluble fractions, res pectively, from D rats compared with that from DR rats using r-P-32 ph osphorylation of appropriate peptide substrates. When measured by West ern blot gel densitometry, particulate PKC-alpha and PKC-delta content increased by 89 and 24%, respectively, but soluble PKC-beta and solub le and particulate PKC-epsilon were unchanged compared with that of DR rats. Similarly, gracilis muscle PKC activity and PKC-alpha and PKC-d elta were elevated in the gracilis muscle, whereas that of the circula ting neutrophil did not differ between the D and DR rats. Thus, in viv o, the early diabetic cardiomyopathy of the D rat is characterized by a restrictive LV with increased septal thickness and is associated wit h elevated PKC activity and increased amounts of myocardial particulat e PKC-alpha and PKC-delta, which are also seen in the skeletal muscle. We conclude that increased PKC isozymes may play a pivotal role durin g IDM in the development of diabetic cardiomyopathy and skeletal muscl e myopathy.