Preservation of base-line hemodynamic function and loss of inducible cardioprotection in adult mice lacking protein kinase C epsilon.
Signaling pathways involving protein kinase C isozymes are modulators of cardiovascular development and response to injury. Protein kinase C epsilon activation in cardiac myocytes reduces necrosis caused by coronary artery disease. However, it is unclear whether protein kinase C epsilon function is required for normal cardiac development or inducible protection against oxidative stress. Protein kinase C delta activation is also observed during cardiac preconditioning. However, its role as a promoter or inhibitor of injury is controversial. We examined hearts from protein kinase C epsilon knock-out mice under physiological conditions and during acute ischemia reperfusion. Null-mutant and wild-type mice displayed equivalent base-line morphology and hemodynamic function. Targeted disruption of the protein kinase C epsilon gene blocked cardioprotection caused by ischemic preconditioning and alpha(1)-adrenergic receptor stimulation. Protein kinase C delta activation increased in protein kinase C epsilon knock-out myocytes without altering resistance to injury. These observations support protein kinase C epsilon activation as an essential component of cardioprotective signaling. Our results favor protein kinase C delta activation as a mediator of normal growth. This study advances the understanding of cellular mechanisms responsible for preservation of myocardial integrity as potential targets for prevention and treatment of ischemic heart disease.
Department of Medicine, University of California, San Francisco, California 94110, USA. gray@medicine.ucsf.edu
Mary O
MO
Gray
Hui-Zhong
HZ
Zhou
Ingeborg
I
Schafhalter-Zoppoth
Peili
P
Zhu
Daria
D
Mochly-Rosen
Robert O
RO
Messing
D000818:Animals; D015153:Blotting, Western; D003433:Crosses, Genetic; D004789:Enzyme Activation; D006321:Heart; D006352:Heart Ventricles / Q000166:cytology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction; D009206:Myocardium / Q000378:metabolism*; D009336:Necrosis; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D015427:Reperfusion Injury; D015398:Signal Transduction; D013997:Time Factors
C497259:Prkcd protein, mouse; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon