Inhibition of protein kinase C reduces left ventricular fibrosis and dysfunction following myocardial infarction.

Abstract

Despite current therapies, chronic heart failure (CHF) remains a major complication of myocardial infarction (MI). The pathological changes that follow MI extend to regions remote from the site of infarction (non-infarct zone, NIZ) where fibrosis is a prominent finding. Although the mechanisms underlying this adverse remodeling are incompletely understood, activation of protein kinase C has recently been implicated in its pathogenesis. MI was induced in Sprague-Dawley rats by ligation of the left anterior descending coronary artery. One week post-MI, animals were randomized to receive the PKC-inhibitor, ruboxistaurin (LY333531) for 4 weeks, or no treatment. When compared with sham-operated animals, post-MI rats showed a 33+/-7% reduction in fractional shortening over a 4 weeks period, that was attenuated by treatment with ruboxistaurin (6+/-11%, P<0.05). Increased matrix deposition was noted in the NIZ, particularly in the subendocardial region of post-MI rats, in association with elevated expression of the profibrotic growth factor, transforming growth factor-beta. These findings were also significantly reduced by ruboxistaurin. PKC-inhibition with ruboxistaurin led to attenuation in both the pathological fibrosis and impaired cardiac function that follow experimental MI, suggesting a possible role for this agent in preventing post-infarction heart failure.

• Authors: Andrew J Boyle, Darren J Kelly, Yuan Zhang, Alison J Cox, Renae M Gow, Kerrie Way, Silviu Itescu, Henry Krum, Richard E Gilbert
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 39 Issue 2 Pg. 213-21 (Aug 2005) ISSN: 0022-2828 [Print] England
• PMID: 15878171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Maleimides
• Transforming Growth Factor beta
• ruboxistaurin
• Collagen
• Protein Kinase C

Topics

• Animals
• Collagen (metabolism)
• Echocardiography
• Extracellular Matrix (metabolism)
• Fibrosis (complications, enzymology)
• Gene Expression Regulation
• Heart Ventricles (diagnostic imaging, pathology)
• In Situ Hybridization
• Indoles (pharmacology)
• Male
• Maleimides (pharmacology)
• Myocardial Infarction (complications, enzymology, pathology, physiopathology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor beta (genetics)
• Ventricular Dysfunction, Left (complications, enzymology, pathology, physiopathology)