| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-Activating Peptide Mimics Ischemic Preconditioning in Aged Hearts Through GSK3
but not F1ATPase Inactivation
1 Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States; Intercollege Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania, United States
2 Intercollege Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania, United States
3 Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: dhk102{at}psu.edu.
In adult heart, selective PKC
activation limits ischemia/reperfusion (I/R) damage and mimics the protection associated with ischemic preconditioning. We sought to determine whether local delivery of an PKC-activator peptide (
RACK) is sufficient to produce a similarly protected phenotype in aged hearts. Langendorff-perfused hearts isolated from adult (5 mo; n=9) and aged (24 mo; n=9) male Fisher 344 rats were perfused with either RACK conjugated to Tat (500 nM) or Tat-only (500 nM) for 10 min prior to global 31 min ischemia. Western blotting was used to measure mitochondrial targeting of PKC, PKC
, p-GSK-3
(ser9) and GSK-3 in hearts snap frozen during I. Recovery of LV developed pressure was significantly improved by RACK (p<0.01) and infarct size reduced in 24 mo vs age-matched controls (60% vs 34%; p<0.01). Mitochondrial PKC levels were 30% greater during I with RACK in aged vs controls (p<0.01). Interestingly, mitochondrial GSK-3 levels were 3-fold greater in aged vs adult during I, and RACK prevented this increase. Mitochondrial p-GSK-3 levels were also greater in aged following RACK (p<0.01), and subsequent inhibition of GSK-3 with SB 216763 (3 µM) prior to I/R elicited protection similar to that observed for RACK (n=3/group). Mitochondrial proteomic analysis further identified group differences in the F1-ATPase- subunit, and coimmunoprecipitation studies revealed a novel interaction with PKC. F1-ATPase-PKC association was affected by ψεRACK in adult but not aged. Our results provide evidence, for the first time, for PKC-mediated protection in aged rat heart following I/R. Our results also suggest a central role for mitochondrial GSK-3 but not the F1ATPase as a potential target of PKC to limit I/R damage with aging.
This article has been cited by other articles:
|
|
 |
|
  M. Juhaszova, D. B. Zorov, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Role of Glycogen Synthase Kinase-3{beta} in Cardioprotection Circ. Res., June 5, 2009; 104(11): 1240 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Peart and J. P. Headrick Clinical cardioprotection and the value of conditioning responses Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1705 - H1720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Murozono, N. Takahashi, T. Shinohara, T. Ooie, Y. Teshima, M. Hara, T. Saikawa, and H. Yoshimatsu Hyperthermia-Induced Cardioprotection Is Potentiated by Ischemic Postconditioning in Rats Experimental Biology and Medicine, May 1, 2009; 234(5): 573 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Akoyev, S. Das, S. Jena, L. Grauer, and D. J. Takemoto Hypoxia-Regulated Activity of PKC{epsilon} in the Lens Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1271 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nguyen, M. Ogbi, and J. A. Johnson Delta Protein Kinase C Interacts with the d Subunit of the F1F0 ATPase in Neonatal Cardiac Myocytes Exposed to Hypoxia or Phorbol Ester: IMPLICATIONS FOR F1F0 ATPase REGULATION J. Biol. Chem., October 31, 2008; 283(44): 29831 - 29840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhai and J. Sadoshima Overcoming an Energy Crisis?: An Adaptive Role of Glycogen Synthase Kinase-3 Inhibition in Ischemia/Reperfusion Circ. Res., October 24, 2008; 103(9): 910 - 913. [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. G. Edwards, M. Y. White, and S. J. Cordwell The Role of Proteomics in Clinical Cardiovascular Biomarker Discovery Mol. Cell. Proteomics, October 1, 2008; 7(10): 1824 - 1837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. O'Brien and S. E. Howlett Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H768 - H777. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
