IMPAIRMENT OF THE SARCOLEMMAL PHOSPHOLIPASE D-PHOSPHATIDATE PHOSPHOHYDROLASE PATHWAY IN DIABETIC CARDIOMYOPATHY

Experimental evidence suggests that the myocardial phospholipase D (PL D)phosphatidate phosphohydrolase (PAP) signalling pathway may regulate Ca2+ movements and contractile performance of the heart. As abnormal Ca2+ homeostasis is associated with diabetic cardiomyopathy, we examin ed the functional status of the PLD/PAP pathway in sarcolemmal (SL) me mbranes isolated from insulin-dependent diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mh/kg b.w.). Comp ared to age-matched controls, SL PLD hydrolytic (producing phosphatidi c acid, PtdOH) and transphosphatidylation activities were significantl y depressed in diabetic animals, while SL PAP was significantly augmen ted. The net effect of the altered enzyme activities in diabetic anima ls was a severely diminished (by 67% of controls) membrane level of PL D-derived PtdOH. Two weeks of insulin therapy to the 6 week diabetic a nimals normalized PLD, while PAP activity and PtdOH level were signifi cantly modified, but had not completely reverted to control values. Th e observed changes were not due to hypothyroidism associated to the di abetic model as the induction of hypothyroidism in healthy non-diabeti c animals did not affect SL PLD and PAP. The results suggest that the severe reduction of PLD-derived PtdOH and increased production of sn-1 ,2-diacylglycerol by phosphatidate phosphohydrolase may lead to an imp airment of the bioprocesses mediated by these signalling lipids. (C) 1 998 Academic Press Limited.