Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes
| Autor: | Danny König, Gunnar Klein, Jörn Tongers, Beate Fiedler, Jörg Heineke, Kai C. Wollert, Helmut Drexler, Suzanne M. Lohmann, Stepan Gambaryan, Tibor Kempf, Theresia Kraft |
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| Rok vydání: | 2004 |
| Předmět: |
MAPK/ERK pathway
MAP Kinase Signaling System Physiology p38 mitogen-activated protein kinases Biology Rats Sprague-Dawley chemistry.chemical_compound NFAT Pathway Physiology (medical) Animals Myocytes Cardiac Enzyme Inhibitors Heme Cells Cultured Cell Size Carbon Monoxide Endothelin-1 NFATC Transcription Factors Calcineurin Biliverdine Nuclear Proteins NFAT Rats Cell biology DNA-Binding Proteins Heme oxygenase Biochemistry chemistry Mitogen-activated protein kinase Heme Oxygenase (Decyclizing) biology.protein Cardiology and Cardiovascular Medicine Heme Oxygenase-1 Signal Transduction Transcription Factors |
| Zdroj: | Cardiovascular Research. 63:545-552 |
| ISSN: | 0008-6363 |
| DOI: | 10.1016/j.cardiores.2004.04.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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