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Cardiovascular Research 2007 73(4):770-782; doi:10.1016/j.cardiores.2006.11.033
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Copyright © 2006, European Society of Cardiology

N-acetylcysteine attenuates PKCβ2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats

Zhengyuan Xiaa,b, Kuo-Hsing Kuoc, Prabhakara R. Nagareddya, Fang Wangb, Zhixin Guoa, Tianhai Guoa, Jihong Jianga and John H. McNeilla,*

aFaculty of Pharmaceutical Sciences, Division of Pharmacology, The University of British Columbia, 2146 East mall, Vancouver, BC, Canada V6T 1Z3
bAnesthesiology Research Laboratory, Department of Anesthesiology, Renmin Hospital, Wuhan University, Wuhan, China
cDepartment of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, Canada V6T 1Z3

* Corresponding author. Tel.: +1 604 822 9373; fax: +1 604 822 8001. Email address: jmcneill{at}interchange.ubc.ca

Objective: Oxidative stress-mediated activation of protein kinase C (PKC) β2 in the myocardium has been implicated in the development of cardiomyopathy. Overexpression of PKCβ2 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 PKCβ2 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 PKCβ2 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-F2t-isoprostane were accompanied by an increased expression of membrane-bound PKCβ2 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 PKCβ2 overexpression represents a mechanism causing hyperglycemia-mediated myocardial hypertrophy, which can be prevented by the antioxidant N-acetylcysteine.

KEYWORDS N-acetylcysteine; Protein kinase C β2; Connective tissue growth factor; Myocardial hypertrophy; Diabetes

Time for primary review 23 days


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