N-acetylcysteine attenuates PKCbeta2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats.
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.
Xia
Zhengyuan
Z
Faculty of Pharmaceutical Sciences, Division of Pharmacology, The University of British Columbia, 2146 East mall, Vancouver, BC, Canada.
Kuo
Kuo-Hsing
KH
Nagareddy
Prabhakara R
PR
Wang
Fang
F
Guo
Zhixin
Z
Guo
Tianhai
T
Jiang
Jihong
J
McNeill
John H
JH
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
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