Protein kinase C in heart failure: a therapeutic target? - PubMed (original) (raw)
Review
. 2009 May 1;82(2):229-39.
doi: 10.1093/cvr/cvp001. Epub 2009 Jan 24.
Affiliations
- PMID: 19168855
- PMCID: PMC2675930
- DOI: 10.1093/cvr/cvp001
Review
Protein kinase C in heart failure: a therapeutic target?
Suresh Selvaraj Palaniyandi et al. Cardiovasc Res. 2009.
Abstract
Heart failure (HF) afflicts about 5 million people and causes 300,000 deaths a year in the United States alone. An integral part of the pathogenesis of HF is cardiac remodelling, and the signalling events that regulate it are a subject of intense research. Cardiac remodelling is the sum of responses of the heart to causes of HF, such as ischaemia, myocardial infarction, volume and pressure overload, infection, inflammation, and mechanical injury. These responses, including cardiomyocyte hypertrophy, myocardial fibrosis, and inflammation, involve numerous cellular and structural changes and ultimately result in a progressive decline in cardiac performance. Pharmacological and genetic manipulation of cultured heart cells and animal models of HF and the analysis of cardiac samples from patients with HF are all used to identify the molecular and cellular mechanisms leading to the disease. Protein kinase C (PKC) isozymes, a family of serine-threonine protein kinase enzymes, were found to regulate a number of cardiac responses, including those associated with HF. In this review, we describe the PKC isozymes that play critical roles in specific aspects of cardiac remodelling and dysfunction in HF.
Figures
Figure 1
Protein kinase C peptide modulators. (A) Inactive protein kinase C (gray) undergoes a conformational change exposing both the RACK-binding site and the active site when diacylglycerol (DG) or PMA are elevated. Active protein kinase C (blue) binds to its RACK (red), anchoring the activated isozyme near its substrate (green). Phosphorylation (P) of that substrate leads to the physiological responses of that isozyme. (B) Alternatively, a peptide that mimics the RACK-binding site, pseudo-RACK (ΨRACK, yellow) can also cause these conformational changes. ΨRACK binds to protein kinase C with a lower affinity than the intact RACK and thus does not always occupy the RACK-binding site on the enzyme. During the time that the peptide is not bound, the activated enzyme may bind to its RACK (red), resulting in anchoring of the activated isozyme near its substrate (green) followed by substrate phosphorylation (P) and physiological responses. This process is isozyme-specific. (C) A peptide corresponding to the RACK-biding site on protein kinase C (orange) inhibits translocation and function of its corresponding isozyme. The translocation inhibitor peptide binds to the RACK and blocks binding of the activated isozyme to that RACK. Therefore, the physiological responses mediated by that isozyme are blocked.
Figure 2
Protein kinase C isozymes are closely involved with different remodelling events in myocardial infarction induced-heart failure. Heart failure progression is noticeably characterized by cardiac remodelling, whereas specific protein kinase C isozyme plays a crucial role in this time-related event. Cardiomyocyte death, inflammation, cardiac hypertrophy, and fibrosis are directly regulated by specific protein kinase C isozymes such as α, βII, δ, and ε protein kinase C as depicted in the figure. The TUNEL staining image is from Murriel et al. (2004) and the hypertrophy image from
.
Figure 3
Schematic protein kinase C isozyme signalling pathways and downstream targets in the heart. The activation of different protein kinase C isozymes contributes to the establishment of heart failure through phosphorylation of isozyme-selective substrates in the failing heart.
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