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

• Published in: Cardiovascular research Vol. 63; no. 3; pp. 545 - 552
• Main Authors: Tongers, Jörn, Fiedler, Beate, König, Danny, Kempf, Tibor, Klein, Gunnar, Heineke, Jörg, Kraft, Theresia, Gambaryan, Stepan, Lohmann, Suzanne M, Drexler, Helmut, Wollert, Kai C
• Format: Journal Article
• Language: English
• Published: England 15.08.2004
• Subjects: 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; Myocytes, Cardiac - metabolism; NFATC Transcription Factors; Nuclear Proteins; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Transcription Factors - metabolism
• ISSN: 0008-6363
• DOI: 10.1016/j.cardiores.2004.04.015

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. 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). 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.