Protein kinase C-delta modulates apoptosis induced by hyperglycemia in adult ventricular myocytes.
We evaluated the direct effect of hyperglycemia on apoptosis of adult rat ventricular myocytes (ARVM) in vitro. Hyperglycemia (16.5 mM) for 24 h increased apoptosis by greater than threefold (48.2 +/- 4.4%, by the TdT-mediated dUTP nick-end labeling method) compared with baseline (14.7 +/- 2.5%). Hyperosmolarity with mannitol (11.0 mM) in the presence of 5.5 mM glucose also increased apoptosis by approximately twofold of baseline. Both glucose and mannitol treatment resulted in the membrane translocation of protein kinase C (PKC)-delta, and the activation of PKC-delta was confirmed by immune complex kinase assay. PKC-delta-specific translocation inhibitor peptide (deltaV1-1) attenuated only apoptosis induced by hyperglycemia but not by mannitol. A PKC-epsilon-specific translocation inhibitor peptide (epsilonV1-1) affected neither type of apoptosis. Moderate overexpression of PKC-delta by adenovirus gene transfer prevented the antiapoptotic effect of deltaV1-1. Furthermore, deltaV1-1 attenuated the production of reactive oxygen species (ROS) by glucose. Taken together, our results indicate that increased ROS production regulated by PKC-delta is in part responsible for the induction of apoptosis by hyperglycemia and that apoptosis by hyperglycemia is mechanistically different from that by hyperosmolarity.
Shizukuda
Yukitaka
Y
Section of Cardiology, Department of Medicine, University of Illinois, Chicago 60612, USA. shizukud@uic.edu
Reyland
Mary E
ME
Buttrick
Peter M
PM
D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D005947:Glucose / Q000008:administration & dosage; D006352:Heart Ventricles / Q000473:pathology; D006943:Hyperglycemia / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008353:Mannitol / Q000008:administration & dosage; D009206:Myocardium / Q000473:pathology*; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D051745:Protein Kinase C-delta; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
D007527:Isoenzymes; D017382:Reactive Oxygen Species; D008353:Mannitol; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D005947:Glucose