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(Hypertension. 2009;54:839.)
© 2009 American Heart Association, Inc.

Original Articles

Involvement of Tissue Transglutaminase in Endothelin 1–Induced Hypertrophy in Cultured Neonatal Rat Cardiomyocytes

Xin Li; Xiao-Li Wei; Ling-Li Meng; Mu-Gen Chi; Jia-Qing Yan; Xiao-Yun Ma; Yong-Sheng Jia; Liang Liang; Hai-Tao Yan; Jian-Quan Zheng

From the Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China.

Correspondence to Jian-Quan Zheng, PhD, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd, Beijing 100850, People’s Republic of China. E-mail zhengjq{at}bmi.ac.cn

A potential link between tissue-type transglutaminase (tTG) and cardiac hypertrophy was suggested recently. However, whether tTG is implicated in hypertrophic agonist-induced cardiac hypertrophy is not yet known. The purpose of this study was to investigate the effects of tTG on cardiomyocyte hypertrophy induced by endothelin (ET) 1. Real-time quantitative RT-PCR and Western blot analysis demonstrated that ET-1 increased the expression of tTG mRNA and protein in cardiomyocytes by activating ET_A receptors. ET-1 failed to cause increases in cell size and [³H]leucine uptake, sarcomere reorganization, and gene induction of the atrial natriuretic factor when cardiomyocytes were treated with monodansylcadaverine, a competitive inhibitor of tTG. Furthermore, the effects of ET-1 on multifunctional activities of tTG were determined by evaluating the incorporation of [³H]putrescine into N,N'-dimethylated casein and charcoal absorption, respectively. The results showed that ET-1 did not influence the basal transglutaminase activity of cardiomyocytes but significantly inhibited the 0.1-mmol/L Ca²⁺-stimulated transglutaminase activity. Otherwise, ET-1 elevated the activity of GTPase in a concentration- and time-dependent manner. In vivo, right ventricular hypertrophy induced by 2 weeks of chronic hypoxia was depressed by the tTG inhibitor cystamine (10 to 30 mg/kg, 2 times per day, IP) in a dose-dependent manner. Taken together, our data strongly supported the notion that tTG may act as a positive regulator of the hypertrophic program in response to ET-1. This is probably attributable to the signaling activity of tTG rather than transglutaminase activity.

Key Words: endothelin • tissue transglutaminase • hypertrophy • sarcomere • G protein • gene expression