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Cardiovascular Research 2004 63(3):545-552; doi:10.1016/j.cardiores.2004.04.015
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes

Jörn Tongersa, Beate Fiedlera, Danny Königa, Tibor Kempfa, Gunnar Kleina, Jörg Heinekea, Theresia Kraftb, Stepan Gambaryanc, Suzanne M Lohmannc, Helmut Drexlera and Kai C Wollert*,a

aDepartment of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany
bDepartment of Molecular and Cellular Physiology, Hannover Medical School, 30625 Hannover, Germany
cInstitute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany

* Corresponding author. Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straβe 1, 30625 Hannover, Germany. Tel.: +49-511-532-4055; fax: +49-511-532-5412. Email address: wollert.kai{at}mh-hannover.de

Objective: Heme oxygenases (HO) are the rate-limiting enzymes in heme degradation, catalyzing the breakdown of heme to equimolar quantities of biliverdin (BV), carbon monoxide (CO), and ferrous iron. The inducible HO isoform, HO-1, confers protection against ischemia/reperfusion (I/R)-injury in the heart. We hypothesized that HO-1 and its catalytic by-products constitute an antihypertrophic signaling module in cardiac myocytes. Methods and results: The G protein-coupled receptor (GPCR) agonist endothelin-1 (ET-1) (30 nmol/l) stimulated a robust hypertrophic response in cardiac myocytes isolated from 1- to 3-day-old Sprague–Dawley rats, with increases in cell surface area (planimetry), sarcomere assembly (confocal laser scanning microscopy), and prepro-atrial natriuretic peptide (ANP) mRNA expression. Adenoviral overexpression of HO-1, but not β-galactosidase, significantly inhibited ET-1 induced cardiac myocyte hypertrophy. The antihypertrophic effects of HO-1 were mimicked by BV (10 µmol/l) and the CO-releasing molecule [Ru(CO)3Cl2]2 (10 µmol/l), strongly suggesting a critical involvement of BV and CO in the antihypertrophic effects of HO-1. Both BV and CO suppressed extracellular signal-regulated kinases (ERK1/ERK2) and p38 mitogen-activated protein kinase (MAPK) activation by ET-1 stimulation. Moreover, BV and CO inhibited the prohypertrophic calcineurin/NFAT pathway. This inhibition occurred upstream from calcineurin because BV and CO inhibited NFAT activation in response to ET-1 stimulation but not in response to adenoviral expression of a constitutively active calcineurin mutant. Upstream-inhibition of the calcineurin/NFAT pathway by CO occurred independent from cGMP and cGMP-dependent protein kinase type I (PKG I). Conclusions: Heme oxygenase-1 and its catalytic by-products, BV and CO, constitute a novel antihypertrophic signaling pathway in cardiac myocytes. Biliverdin and CO inhibition of MAPKs and calcineurin/NFAT signaling provides a mechanistic framework how heme degradation products may promote their antihypertrophic effects.

KEYWORDS Hypertrophy; Second messengers; Signal transduction; MAP kinase; Calcium (cellular)

Time for primary review 25 days


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