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(Circulation. 2004;110:309-316.)
© 2004 American Heart Association, Inc.

Original Articles

Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo

Chien-Ming Hu, PhD; Yen-Hui Chen, DVM, VMDr; Ming-Tsai Chiang, MS; Lee-Young Chau, PhD

From the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.

Correspondence to Lee-Young Chau, PhD, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China. E-mail lyc{at}ibms.sinica.edu.tw

Received September 1, 2003; de novo received January 27, 2004; revision received April 1, 2004; accepted April 4, 2004.

Background— Heme oxygenase-1 (HO-1) is a stress-response enzyme implicated in cardioprotection. To explore whether HO-1 has a role in cardiac remodeling response, the effect of its overexpression on angiotensin II (Ang II)-induced cardiac hypertrophy was examined.

Methods and Results— HO-1 was induced in cultured rat neonatal cardiomyocytes by treatment with cobalt protoporphyrin IX (CoPPIX) or a recombinant adenovirus carrying the human HO-1 gene. Ang II-induced myocyte hypertrophy assessed by increments in cell size, [³H]leucine uptake, and protein content was suppressed by HO-1 overexpression. Cotreatment of cells with tin protoporphyrin IX, a HO inhibitor, significantly reversed the suppressive effect of HO-1. Bilirubin, one of the byproducts of heme degradation by HO-1, mediated the suppressive effect through the inhibition of Ang II-induced production of reactive oxygen species, as detected by a 2',7'-dichlorofluorescein probe. The antihypertrophic effect of HO-1 was also demonstrated in rats receiving chronic Ang II infusions. Cotreatment of animals with CoPPIX significantly attenuated Ang II-induced left ventricular hypertrophy and hyperdynamic contractions, whereas concomitant treatment with tin protoporphyrin IX abolished CoPPIX-mediated cardioprotection in vivo.

Conclusions— HO-1 attenuates Ang II-induced cardiac hypertrophy both in vitro and in vivo, and bilirubin mediates, at least in part, the antihypertrophic effect of HO-1 via inhibition of reactive oxygen species production after Ang II stimulation.

Key Words: heme oxygenase • angiotensin • hypertrophy

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