title: Inhibition of protein kinase C-beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy.
abstract: 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 beta-adrenergic systems are being sought. One such target is the beta-isoform of protein kinase C (PKC), implicated in both the complications of diabetes and in cardiac dysfunction in the nondiabetic setting.
  
  
  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-beta would preserve cardiac function and reduce structural injury. Diabetic rats were randomized to receive either vehicle or the PKC-beta 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-beta 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-beta inhibition may represent a novel therapeutic strategy for the prevention of diabetes-associated cardiac dysfunction.
authors.affiliation: Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: David L
authors.initials: DL
authors.lastname: Prior
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006328:Cardiac Catheterization; D009202:Cardiomyopathies / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003971:Diastole; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006720:Homozygote; D006984:Hypertrophy; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D018384:Oxidative Stress; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D003094:Collagen; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D020033:Protein Isoforms; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D012083:Renin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D051899:Smad2 Protein; D000099211:Phospholamban; C535029:Ren2 protein, rat; C497784:Smad2 protein, rat; C099154:ruboxistaurin