title: Selective inhibition of protein kinase C beta(2) attenuates inducible nitric oxide synthase-mediated cardiovascular abnormalities in streptozotocin-induced diabetic rats.
abstract: OBJECTIVE
  Impaired cardiovascular function in diabetes is partially attributed to pathological overexpression of inducible nitric oxide synthase (iNOS) in cardiovascular tissues. We examined whether the hyperglycemia-induced increased expression of iNOS is protein kinase C-beta(2) (PKCbeta(2)) dependent and whether selective inhibition of PKCbeta reduces iNOS expression and corrects abnormal hemodynamic function in streptozotocin (STZ)-induced diabetic rats.
  
  
  METHODS
  Cardiomyocytes and aortic vascular smooth muscle cells (VSMC) from nondiabetic rats were cultured in low (5.5 mmol/l) or high (25 mmol/l) glucose or mannitol (19.5 mmol/l mannitol + 5.5 mmol/l glucose) conditions in the presence of a selective PKCbeta inhibitor, LY333531 (20 nmol/l). Further, the in vivo effects of PKCbeta inhibition on iNOS-mediated cardiovascular abnormalities were tested in STZ-induced diabetic rats.
  
  
  RESULTS
  Exposure of cardiomyocytes to high glucose activated PKCbeta(2) and increased iNOS expression that was prevented by LY333531. Similarly, treatment of VSMC with LY333531 prevented high glucose-induced activation of nuclear factor kappaB, extracellular signal-related kinase, and iNOS overexpression. Suppression of PKCbeta(2) expression by small interference RNA decreased high-glucose-induced nuclear factor kappaB and extracellular signal-related kinase activation and iNOS expression in VSMC. Administration of LY333531 (1 mg/kg/day) decreased iNOS expression and formation of peroxynitrite in the heart and superior mesenteric arteries and corrected the cardiovascular abnormalities in STZ-induced diabetic rats, an action that was also observed with a selective iNOS inhibitor, L-NIL.
  
  
  CONCLUSIONS
  Collectively, these results suggest that inhibition of PKCbeta(2) may be a useful approach for correcting abnormal hemodynamics in diabetes by preventing iNOS mediated nitrosative stress.
authors: Faculty of Pharmaceutical Sciences, The University of British Columbia, British Columbia, Canada.
authors: Prabhakara Reddy
authors: PR
authors: Nagareddy
authors: Hesham
authors: H
authors: Soliman
authors: Guorong
authors: G
authors: Lin
authors: Padmesh S
authors: PS
authors: Rajput
authors: Ujendra
authors: U
authors: Kumar
authors: John H
authors: JH
authors: McNeill
authors: Kathleen M
authors: KM
authors: MacLeod
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008353:Mannitol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C090663:N(6)-(1-iminoethyl)lysine; D008353:Mannitol; C099154:ruboxistaurin; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose; D008239:Lysine