Protein kinase C (PKC) isozymes play a key role in insult-induced cardiac remodeling and the progression to heart failure (HF). Conflicting data on the role of individual PKC isozymes in modulating these functions have been reported, in part due to the use of PKC isozyme non-selective pharmacological tools. Our research identified PKC isozyme-selective inhibitors and activators, which we apply to determine the role of individual isozymes in normal and diseased heart. We identified peptide inhibitors and activators for each isozyme and found that the peptides can be effectively delivered into the heart, in vivo. Using these PKC regulating peptides, we previously showed opposing roles for specific PKC isozymes in various functions; we showed that ePKC activation or delta PKC inhibition provides cardioprotection from ischemia in vitro, ex vivo and recently in vivo. We also found that our isozyme-specific peptide regulators of PKC remain effective when continuously delivered in vivo, for 10 days. Therefore, for the first time, we can determine whether these PKC-regulating peptides can prevent, enhance or reduce cardiac remodeling and transition to heart failure, a study that requires regulation of PKC in a sustained fashion. Due to the limitations of animal models for cardiac remodeling and HF, we plan to use 3 different models, and use the peptides as selective pharmacological tools to determine the role of each PKC isozyme in the development of HF. The first model involves pressure overload using transverse aortic constriction in mice. The second uses pressure overload in hypertensive Dahl rats, which develop reliable cardiac remodeling and heart failure after initiation of a high salt diet. The third model follows post myocardial infarction-induced cardiac remodeling and HF in mice. Peptide regulators of individual isozymes (activators or inhibitors) will be delivered in a sustained fashion at different times during the course of the disease to determine the role of each PKC isozyme in the development of adaptive and maladaptive remodeling and the transition to heart failure. Together, these studies will identify the PKC isozyme(s) that should be targeted for the development of new therapeutics for human heart failure, especially if PKC-based pharmacotherapy is considered

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076675-04
Application #
7214740
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Przywara, Dennis
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$376,321
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Ferreira, Julio Cesar Batista; Brum, Patricia Chakur; Mochly-Rosen, Daria (2011) ?IIPKC and ?PKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J Mol Cell Cardiol 51:479-84
Ferreira, Julio C B; Koyanagi, Tomoyoshi; Palaniyandi, Suresh S et al. (2011) Pharmacological inhibition of *IIPKC is cardioprotective in late-stage hypertrophy. J Mol Cell Cardiol 51:980-7
Palaniyandi, Suresh Selvaraj; Ferreira, Julio Cesar Batista; Brum, Patricia Chakur et al. (2011) PKC*II inhibition attenuates myocardial infarction induced heart failure and is associated with a reduction of fibrosis and pro-inflammatory responses. J Cell Mol Med 15:1769-77
Palaniyandi, Suresh Selvaraj; Qi, Xin; Yogalingam, Gouri et al. (2010) Regulation of mitochondrial processes: a target for heart failure. Drug Discov Today Dis Mech 7:e95-e102
Palaniyandi, Suresh Selvaraj; Sun, Lihan; Ferreira, Julio Cesar Batista et al. (2009) Protein kinase C in heart failure: a therapeutic target? Cardiovasc Res 82:229-39
Inagaki, Koichi; Koyanagi, Tomoyoshi; Berry, Natalia C et al. (2008) Pharmacological inhibition of epsilon-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure. Hypertension 51:1565-9
Palaniyandi, Suresh Selvaraj; Inagaki, Koichi; Mochly-Rosen, Daria (2008) Mast cells and epsilonPKC: a role in cardiac remodeling in hypertension-induced heart failure. J Mol Cell Cardiol 45:779-86
Churchill, Eric; Budas, Grant; Vallentin, Alice et al. (2008) PKC isozymes in chronic cardiac disease: possible therapeutic targets? Annu Rev Pharmacol Toxicol 48:569-99
Kim, Jeewon; Choi, Yoon-La; Vallentin, Alice et al. (2008) Centrosomal PKCbetaII and pericentrin are critical for human prostate cancer growth and angiogenesis. Cancer Res 68:6831-9

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