Published online before print February 10, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.765750
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Original Articles |
Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy
From the Keenan Research Centre in the Li Ka Shing Knowledge Institute (K.A.C., A.A., K.T., R.E.G.), St Michael’s Hospital and University of Toronto, Toronto, Canada; Department of Medicine (K.A.C., D.J.K., Y.Z., A.J.C., R.E.G.), University of Melbourne, St Vincent’s Hospital; Cardiac Investigation Unit (D.L.P.), St. Vincent’s Hospital Melbourne; and NHMRC CCRE in Therapeutics (H.K.), Department of Epidemiology and Preventive Medicine and Department of Medicine, Monash University, Faculty of Medicine, Nursing and Health Sciences, The Alfred, Victoria, Australia.
Correspondence to Richard E. Gilbert, MD, PhD, St Michael’s Hospital, Room 6-138, 61 Queen Street, Toronto, Ontario, Canada M5C 2T2. E-mail richard.gilbert{at}utoronto.ca
Received January 15, 2008; accepted January 15, 2009.
Background— Heart failure is a common cause of morbidity and mortality in diabetic patients that frequently manifests in the absence of impaired left ventricular systolic function. In contrast to the strong evidence base for the treatment of systolic heart failure, the treatment of heart failure with preserved left ventricular function is uncertain, and therapeutic targets beyond blockade of the renin-angiotensin-aldosterone and β-adrenergic systems are being sought. One such target is the β-isoform of protein kinase C (PKC), implicated in both the complications of diabetes and in cardiac dysfunction in the nondiabetic setting.
Methods and Results— Using a hemodynamically validated rodent model of diabetic diastolic heart failure, the (mRen-2)27 transgenic rat, we sought to determine whether selective inhibition of PKC-β would preserve cardiac function and reduce structural injury. Diabetic rats were randomized to receive either vehicle or the PKC-β inhibitor, ruboxistaurin (20 mg/kg per d) and followed for 6 weeks. Compared with untreated animals, ruboxistaurin-treated diabetic rats demonstrated preserved systolic and diastolic function, as measured by the slope of preload recruitable stroke work relationship (P<0.05) and the slope of the end-diastolic pressure volume relationship (P<0.01). Collagen I deposition and cardiomyocyte hypertrophy were both reduced in diabetic animals treated with ruboxistaurin (P<0.01), as was phosphorylated-Smad2, an index of transforming growth factor-β activity (P<0.01 for all, versus untreated diabetic rats).
Conclusions— PKC-ß inhibition attenuated diastolic dysfunction, myocyte hypertrophy, and collagen deposition and preserved cardiac contractility. PKC-β inhibition may represent a novel therapeutic strategy for the prevention of diabetes-associated cardiac dysfunction.
Key Words: cardiomyopathy • diabetes mellitus • pharmacology
CLINICAL PERSPECTIVE
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- Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy
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Circ Heart Fail 2009 2: 129-137.[Abstract] [Full Text] [PDF]