EXPERIMENTAL DIABETES IS ASSOCIATED WITH FUNCTIONAL ACTIVATION OF PROTEIN-KINASE C-EPSILON AND PHOSPHORYLATION OF TROPONIN-I IN THE HEART, WHICH ARE PREVENTED BY ANGIOTENSIN-II RECEPTOR BLOCKADE

A cardiomyopathy that is characterized by an impairment in diastolic r elaxation and a loss of calcium sensitivity of the isolated myofibril has been described in chronic diabetic animals and humans. To explore a possible role for protein kinase C (PKC)-mediated phosphorylation of myofibrillar proteins in this process, we characterized the subcellul ar distribution of the major PKC isoforms seen in the adult heart in c ardiocytes isolated from diabetic rats and determined patterns of phos phorylation of the major regulatory proteins, including troponin I (Tn I). Rats were made diabetic with a single injection of streptozotocin, and myocardiocytes were isolated and studied 3 to 4 weeks later. In n ondiabetic animals, 76% of the PKC epsilon isoform was located in the cytosol and 24% was particulate, whereas in diabetic animals, 55% was cytosolic and 45% was particulate (P<.05). PKC delta, the other major PKC isoform seen in adult cardiocytes, did not show a change in subcel lular localization. In parallel, TnI phosphorylation was increased 5-f old in cardiocytes isolated from the hearts of diabetic animals relati ve to control animals (P<.01). The change in PKC epsilon distribution and in TnI phosphorylation in diabetic animals was completely prevente d by rendering the animals euglycemic with insulin or by concomitant t reatment with a specific angiotensin II type-1 receptor (AT(1)) antago nist. Since PKC phosphorylation of TnI has been associated with a loss of calcium sensitivity of intact myofibrils, these data suggest that angiotensin II receptor-mediated activation of PKC may play a role in the contractile dysfunction seen in chronic diabetes.