Inhibition of PKCα/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury - PubMed (original) (raw)
Inhibition of PKCα/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury
Dennis Ladage et al. Circ Res. 2011.
Abstract
Rationale: Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats.
Objective: Large and small mammals differ in several key indexes of heart function and biochemistry, lending uncertainty as to how PKCα/β inhibition might affect or protect a large animal model of heart failure.
Methods and results: We demonstrate that ruboxistaurin administration to a pig model of myocardial infarction-induced heart failure was protective. Twenty-kilogram pigs underwent left anterior descending artery occlusion resulting in myocardial infarctions and were then divided into vehicle or ruboxistaurin feed groups, after which they were monitored monthly for the next 3 months. Ruboxistaurin administered pigs showed significantly better recovery of myocardial contractility 3 months after infarction injury, greater ejection fraction, and greater cardiac output compared with vehicle-treated pigs.
Conclusions: These results provide additional evidence in a large animal model of disease that PKCα/β inhibition (with ruboxistaurin) represents a tenable and novel therapeutic approach for treating human heart failure.
Figures
Figure 1
Ruboxistaurin attenuates heart failure in pigs post MI. A, Millar catheter-based analysis of heart rate and B, contractility in vehicle or ruboxistaurin treated (10 mg/kg/day) pigs subjected to MI injury at the indicated times after injury (days or months). #P<0.05 versus 0 time point. *P<0.05 versus vehicle treated pigs at 3 months. C, left ventricular ejection fraction measured by ventriculography in vehicle or ruboxistaurin treated pigs after MI for the indicated periods of time (days or months). *P<0.05 versus vehicle at 3 months. D, Cardiac output measured with a Swan Ganz catheter in vehicle or ruboxistaurin treated pigs after MI for the indicated periods of time. *P<0.05 versus vehicle at 3 months. E, Quantitation of scar size after TTC staining to show area of injury between the 2 groups. N.S.=not significantly different. F, Pig heart slices after MI injury stained with TTC (white area is not stained by TTC and represents the area of infraction).
Figure 2
Western blot analysis of calcium handling proteins, myofilament proteins, and PKCα/β/γ for the native protein or for the indicated specific phosphorylation site from pig hearts after 3 months of ruboxistaurin treatment or no treatment after myocardial infarction injury. One non-infarcted control is shown. The indicated proteins or phosphoproteins were analyzed from pieces of anterior or inferior portions of the left ventricle. The “-P” designation represents specialized gel electrophoresis conditions that separate proteins with differential phosphorylation.
Comment in
- PKC-ing is believing: targeting protein kinase C in heart failure.
Belmonte SL, Blaxall BC. Belmonte SL, et al. Circ Res. 2011 Dec 9;109(12):1320-2. doi: 10.1161/CIRCRESAHA.111.259358. Circ Res. 2011. PMID: 22158646 No abstract available.
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References
- Churchill E, Budas G, Vallentin A, Koyanagi T, Mochly-Rosen D. PKC isozymes in chronic cardiac disease: possible therapeutic targets? Annu Rev Pharmacol Toxicol. 2008;48:569–599. - PubMed
- Pass JM, Gao J, Jones WK, Wead WB, Wu X, Zhang J, Baines CP, Bolli R, Zheng YT, Joshua IG, Ping P. Enhanced PKC beta II translocation and PKC beta II-RACK1 interactions in PKC epsilon-induced heart failure: a role for RACK1. Am J Physiol Heart Circ Physiol. 2001;281:H2500–H2510. - PubMed
- Ping P, Zhang J, Qiu Y, Tang XL, Manchikalapudi S, Cao X, Bolli R. Ischemic preconditioning induces selective translocation of protein kinase C isoforms epsilon and eta in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res. 1997;81:404–414. - PubMed
- Hambleton M, Hahn H, Pleger ST, Kuhn MC, Klevitsky R, Carr AN, Kimball TF, Hewett TE, Dorn GW, 2nd, Koch WJ, Molkentin JD. Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure. Circulation. 2006;114:574–582. - PMC - PubMed
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