Phosphoinositide-phospholipase C in diabetic cardiomyopathy

Abstract

In the heart, stimulation of many receptors, including those for angiotensin II (Ang II), endothelin-1 (ET-1), catacholamines and polypeptide growth factors, is associated with the activation of phospholipase C (PLC) and subsequent hydrolysis of phosphatidylinosiltol 4,5-bisphosphate (PtdIns(4,5)$P\sb2).$ The two second messengers produced in this reaction, namely sn-1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (Ins(1,4,5)$P\sb3),$ are involved in the regulation of cardiac contractility and intracellular Ca$\sp{2+}$ concentration. Phosphatidic acid (PtdOH) has been demonstrated to stimulate cardiac PLC$\gamma$1 and PLC$\delta$1 activities. In addition, decreased sarcolemma (SL) phospholipase D (PLD)-derived PtdOH levels and decreased PtdOH-induced positive inotropic effects in the diabetic heart have also been reported. Therefore, it is hypothesized that a decreased stimulation by PtdOH might result in a decreased PLC activity during diabetic cardiomyopathy. In this study, the effect of PtdOH on the phosphoinositide-PLC pathway were examined in isolated SL and cardiomyocytes from 8-week chronic insulin-dependent diabetic rats induced by a single intravenous injection of streptozotocin (STZ, 65 mg/kg body weight). The beneficial effect of insulin on this pathway was assessed in 6-week diabetic rats with 2-week insulin treatment. The activity and relative protein amount of PLC$\gamma$1, one of the prominent cardiac PLC isoforms, were also studied. (Abstract shortened by UMI.)