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

Abstract

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 beta-galactosidase, significantly inhibited ET-1 induced cardiac myocyte hypertrophy. The antihypertrophic effects of HO-1 were mimicked by BV (10 micromol/l) and the CO-releasing molecule [Ru(CO)3Cl2]2 (10 micromol/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.

• Authors: Jörn Tongers, Beate Fiedler, Danny König, Tibor Kempf, Gunnar Klein, Jörg Heineke, Theresia Kraft, Stepan Gambaryan, Suzanne M Lohmann, Helmut Drexler, Kai C Wollert
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 63 Issue 3 Pg. 545-52 (Aug 15 2004) ISSN: 0008-6363 [Print] England
• PMID: 15276480 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copryright 2004 European Society of Cardiology

Chemical References

• DNA-Binding Proteins
• Endothelin-1
• Enzyme Inhibitors
• NFATC Transcription Factors
• Nuclear Proteins
• Transcription Factors
• Carbon Monoxide
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• Calcineurin
• Biliverdine

Topics

• Animals
• Biliverdine (pharmacology)
• Calcineurin (metabolism)
• Carbon Monoxide (pharmacology)
• Cell Size (drug effects)
• Cells, Cultured
• DNA-Binding Proteins (metabolism)
• Endothelin-1 (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Heme Oxygenase (Decyclizing) (pharmacology)
• Heme Oxygenase-1
• MAP Kinase Signaling System (drug effects)
• Myocytes, Cardiac (drug effects, metabolism)
• NFATC Transcription Factors
• Nuclear Proteins
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)