Inhibition of protein kinase C reduces left ventricular fibrosis and dysfunction following myocardial infarction.
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.
Boyle
Andrew J
AJ
Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Princes Street, Fitzroy 3065, Vic., Australia.
Kelly
Darren J
DJ
Zhang
Yuan
Y
Cox
Alison J
AJ
Gow
Renae M
RM
Way
Kerrie
K
Itescu
Silviu
S
Krum
Henry
H
Gilbert
Richard E
RE
D000818:Animals; D003094:Collagen / Q000378:metabolism; D004452:Echocardiography; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000150:complications / Q000201:enzymology*; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*
D007211:Indoles; D008301:Maleimides; D016212:Transforming Growth Factor beta; C099154:ruboxistaurin; D003094:Collagen; D011493:Protein Kinase C