title: N-acetylcysteine attenuates PKCbeta2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats.
abstract: OBJECTIVE
  Oxidative stress-mediated activation of protein kinase C (PKC) beta(2) in the myocardium has been implicated in the development of cardiomyopathy. Overexpression of PKCbeta(2) is associated with increased expression of connective tissue growth factor (CTGF) in myocardium, resulting in myocardial hypertrophy. We hypothesized that chronic treatment with the antioxidant N-acetylcysteine (NAC) would normalize oxidative stress-mediated overexpression of myocardial PKCbeta(2) and CTGF and attenuate the development of myocardial hypertrophy.
  
  
  METHODS
  Control and streptozotocin-induced diabetic rats were treated with NAC in drinking water for 8 weeks. At termination rats were surgically prepared for hemodynamic measurement, subsequent to which their hearts were removed to evaluate cardiac performance and histological and biochemical changes. Further, the role of PKCbeta(2) in hyperglycemia-induced cardiomyocyte hypertrophy was tested in cultured neonatal cardiomyocytes.
  
  
  RESULTS
  Myocardial hypertrophy, characterized by an increased ratio of ventricle weight to body weight and cardiomyocyte cross-sectional area was found to be higher in untreated diabetic rats. Further, in myocardium, increased levels of 15-F(2t)-isoprostane were accompanied by an increased expression of membrane-bound PKCbeta(2) and CTGF. N-acetylcysteine treatment not only attenuated these changes but also prevented hyperglycemia-induced hypertrophy in cultured neonatal rat cardiomyocytes.
  
  
  CONCLUSIONS
  The results suggest that PKCbeta(2) overexpression represents a mechanism causing hyperglycemia-mediated myocardial hypertrophy, which can be prevented by the antioxidant N-acetylcysteine.
authors.affiliation: Faculty of Pharmaceutical Sciences, Division of Pharmacology, The University of British Columbia, 2146 East mall, Vancouver, BC, Canada.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
authors.forename: Kuo-Hsing
authors.initials: KH
authors.lastname: Kuo
authors.forename: Prabhakara R
authors.initials: PR
authors.lastname: Nagareddy
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Guo
authors.forename: Tianhai
authors.initials: T
authors.lastname: Guo
authors.forename: Jihong
authors.initials: J
authors.lastname: Jiang
authors.forename: John H
authors.initials: JH
authors.lastname: McNeill
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000032:analysis; D024043:Collagen Type II / Q000032:analysis; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000032:analysis / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000032:analysis
chemical_list: D000975:Antioxidants; C526316:CCN2 protein, rat; D024042:Collagen Type I; D024043:Collagen Type II; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D013481:Superoxides; D055513:Connective Tissue Growth Factor; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose; D000111:Acetylcysteine