Christopher P. Baines, Ph.D.
Postdoctoral Fellow

e-mail: cpbaines@gmx.net

Research Interests:

Mitochondrial PKC signaling in cardioprotection.

The mitochondrion has received considerable attention as the target of multiple forms of protection, such as preconditioning (PC), against myocardial ischemia/reperfusion injury. Pharmacological studies have implicated a role for mitochondrial KATP channel opening in cardioprotection, and PC has been shown to preserve mitochondrial function and to reduce cytochrome c release in response to ischemia/reperfusion. In addition, multiple studies have also demonstrated that activation of the signaling kinase PKC is critical for the protective phenotype, and cardioprotective stimuli induce translocation of PKC to mitochondria. Accordingly, mitochondrial proteins must be targets for PKC, and may play a role in cardioprotection. However, the identities of the mitochondrial proteins influenced by PKC have yet to be ascribed. Consequently, my research is concerned with: 1) how does PKC interact with the cardiac mitochondrion; 2) what are the identities of the mitochondrial proteins modulated by PKC; and 3) how do these mitochondrial modulations contribute to cardioprotection. We have recently shown in PKC transgenic mice, which are chronically cardioprotected, that mitochondrial PKC expression and activity are significantly enhanced. This in turn, upregulates the ability of PKC to interact with and activate mitochondrial mitogen-activated protein kinases, ultimately leading to the phosphorylation and inactivation of the pro-death protein, Bad. In addition, we have found that PKC can directly bind to and inhibit the mitochondrial permeability transition pore, opening of which has been purported to contribute to ischemia/reperfusion injury. Delineation of mitochondrial PKC signaling will hopefully provide novel targets for the development of therapeutic strategies to improve cardiomyocyte function and survival.

Publications:

1. Baines CP, Song CX, Guo Y, Bolli R, Wang O-L, Zheng Y-T, Xiu JX, Cardwell EM, Ping P. Protein kinase C interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003 Mar 27; [epub ahead of print]

2. Hojo Y, Saito Y, Tanimoto T, Hoefen RJ, Baines CP, Yamamoto K, Haendeler J, Asmis R, Berk BC. Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism. Circ Res. 2002;91:712-8.

3. Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P. Mitochondrial PKC and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCe-MAPK interactions and differential MAPK activation in PKCe-induced cardioprotection. Circ Res. 2002;90:390-397.

4. Pass JM, Gao J, Jones WK, Wead WB, Wu X, Zhang J, Baines CP, Bolli R, Zheng Y-T, Ping P. Enhanced PKCbII translocation and PKCbII-RACK1 interactions in PKCe-induced cardiac hypertrophy and failure: a role for RACK1. Am J Physiol. 2001;281:H2500-2510.

5. Krenz M, Baines CP, Heusch G, Downey JM, Cohen MV. Alcohol induces cardioprotection via activation of protein kinases but not mitochondrial KATP channels in rabbits. J Mol Cell Cardiol. 2001;33:2015-2022.

6. Takeishi Y, Huang Q, Wang, T, Glassman M, Yoshizumi M, Baines CP, Lee J-D, Kawakastu H, Che W, Lerner-Marmarosh N, Zhang C, Ohta S, Walsh RA, Berk BC, Abe J-I. Src family kinase and adenosine regulate multiple MAP kinases in ischemic myocardium: modulation of MAP kinases activation by ischemic preconditioning. J Mol Cell Cardiol. 2001;33:1989-2005.

7. Vondriska TM, Zhang J, Song C, Tang X-L, Cao X, Baines CP, Pass JM, Wang S, Bolli R, Ping P. PKC-Src modules direct signal transduction in NO-induced cardioprotection: complex formation as a means for cardioprotective signaling. Circ Res. 2001;88:1306-1313.

8. Baines CP, Pass JM, Ping P. Protein kinases and kinase-modulated effectors in the late phase of ischemic preconditioning. Basic Res Cardiol. 2001;96:207-218.

9. Krenz M, Baines CP, Heusch G, Cohen MV, Downey JM. Transient, but not sustained, ethanol exposure mimics ischemic preconditioning in rabbit hearts. J Am Coll Cardiol. 2001;37:601-607.

10. Cohen MV, Baines CP, Downey JM. Ischemic preconditioning: from adenosine receptor to KATP channel. Annu Rev Physiol. 2000;62:79-109.

11. Abe J-I, Baines CP, Berk BC. Role of mitogen-activated protein kinases in ischemia and reperfusion-injury: the good and the bad. Circ. Res. 2000;86:607-609.

12. Nakano A, Baines CP, Kim SO, Pelech SL, Downey JM, Cohen MV, Critz SD. Ischemic preconditioning activates MAPKAPK2, but not JNK, in the isolated rabbit heart: evidence for involvement of p38 MAPK. Circ.Res. 2000;86:144-151.

13. Baines CP, Liu GS, Birincioglu M, Critz SD, Cohen MV, Downey JM. Ischemic preconditioning is associated with interaction between mitochondrial KATP-channels and the actin cytoskeleton in the rabbit myocardium. Am J Physiol. 1999;276:H1361-H1368.

14. Kim SO, Baines CP, Critz SD, Pelech SL, Katz S, Downey JM, Cohen MV. Ischemia induced activation of heat shock protein 27 kinases and casein kinase 2 in the preconditioned rabbit heart. Biochem Cell Biol. 1999;77:559-67.

15. Baines CP, Cohen MV, Downey JM. Signal transduction in ischemic preconditioning: the role of kinases and mitochondrial KATP-channels. J Cardiovasc Electrophys. 1999;10:741-754.

16. Baines CP, Wang L, Cohen MV, Downey JM. Myocardial protection by insulin is dependent on phosphatidylinositol 3-kinase but not protein kinase C or KATP-channels in the isolated rabbit heart. Basic Res Cardiol. 1999;94:188-198.

17. Baines CP, Wang L, Cohen MV, Downey JM. Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning's anti-infarct effect in the rabbit heart. J Mol Cell Cardiol. 1998;30:383-392.

18. Weinbrenner C, Baines CP, Liu GS, Armstrong SC, Ganote CE, Walsh AH, Honkanen RE, Cohen MV, Downey JM. Fostriecin, an inhibitor of protein phosphatase 2A, limits myocardial infarction even when administered after onset of ischemia. Circulation. 1998;98:899-905.

19. Baines CP, Goto M, Downey JM. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol. 1997;29:207-216.

20. Baines CP, Szwarc RS, Ball HA. Parallel tolerance between platelet cyclic GMP and preload effects of nitroglycerine in anaesthetized mini-pigs. Br J Pharmacol. 1994;113:334-335.