Defective phosphatidic acid-phospholipase C signaling in diabetic cardiomyopathy.
The effects of exogenous phosphatidic acid (PA) on Ca2+ transients and contractile activity were studied in cardiomyocytes isolated from chronic streptozotocin-induced diabetic rats. In control cells, 25 microM PA induced a significant increase in active cell shortening and Ca2+ transients. PA increased IP3 generation in the control cardiomyocytes and its inotropic effects were blocked by a phospholipase C inhibitor. In cardiomyocytes from diabetic rats, PA induced a 25% decrease in active cell shortening and no significant effect on Ca2+ transients. Basal and PA-induced IP3 generation in diabetic rat cardiomyocytes was 3-fold lower as compared to control cells. Sarcolemmal membrane PLC activity was impaired. Insulin treatment of the diabetic animals resulted in a partial recovery of PA responses. Our results, therefore, identify an important defect in the PA-PLC signaling pathway in diabetic rat cardiomyocytes, which may have significant implications for heart dysfunction during diabetes.
Tappia
Paramjit S
PS
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Canada.
Maddaford
Thane G
TG
Hurtado
Cecilia
C
Dibrov
Elena
E
Austria
J Alejandro
JA
Sahi
Nidhi
N
Panagia
Vincenzo
V
Pierce
Grant N
GN
D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010712:Phosphatidic Acids / Q000494:pharmacology*; D054803:Phospholipase C delta; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism*
D007527:Isoenzymes; D010712:Phosphatidic Acids; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D054803:Phospholipase C delta; D002118:Calcium