Abstract |
Carbon monoxide (CO) is one of the cytoprotective byproducts of heme oxygenase (HO)-1 and exerts anti-inflammatory action in various models. However, the detailed mechanisms underlying CO-induced HO-1 expression in primary human cardiomyocytes remain largely unidentified. We used primary left ventricle myocytes as a model and applied CO releasing molecule (CORM)-2 to investigate the relationship of CO and HO-1 expression. We herein used Western blot, real-time PCR, promoter activity and EIA to investigate the role of HO-1 expression protecting against thrombin-mediated responses. We found that thrombin-induced COX-2 expression, PGE2 release and cardiomyocyte hypertrophy markers (increase in ANF/BNP, α-actin expression and cell surface area) was attenuated by pretreatment with CORM-2 which was partially reversed by hemoglobin (Hb) or ZnPP (an inhibitor of HO-1 activity), suggesting that HO-1/CO system may be of clinical importance to ameliorate heart failure through inhibition of inflammatory responses. CORM-2-induced HO-1 protein expression, mRNA and promoter was attenuated by pretreatment with the inhibitors of Pyk2 (PF431396), PDGFR ( AG1296), PI3K ( LY294002), Akt (SH-5), p38 (SB202530), JNK1/2 ( SP600125), FoxO1 ( AS1842856) and Sp1 ( mithramycin A). The involvement of these signaling components was further confirmed by transfection with respective siRNAs, consistent with those of pharmacological inhibitors. These results suggested that CORM-2-induced HO-1 expression is mediated through a Pyk2/PDGFR/PI3K/Akt/FoxO1/Sp1-dependent manner and exerts a cytoprotective effect in human cardiomyocytes.
|
Authors | Peter Tzu-Yu Chien, Chih-Chung Lin, Li-Der Hsiao, Chuen-Mao Yang |
Journal | Toxicology and applied pharmacology
(Toxicol Appl Pharmacol)
Vol. 289
Issue 2
Pg. 349-59
(Dec 01 2015)
ISSN: 1096-0333 [Electronic] United States |
PMID | 26385185
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- Actins
- Enzyme Inhibitors
- Organometallic Compounds
- tricarbonyldichlororuthenium (II) dimer
- Natriuretic Peptide, Brain
- Carbon Dioxide
- Atrial Natriuretic Factor
- HMOX1 protein, human
- Heme Oxygenase-1
- Cyclooxygenase 2
- PTGS2 protein, human
- Thrombin
- Dinoprostone
|
Topics |
- Actins
(metabolism)
- Atrial Natriuretic Factor
(metabolism)
- Carbon Dioxide
(metabolism, pharmacology)
- Cardiomegaly
(chemically induced, enzymology, genetics, pathology, prevention & control)
- Cells, Cultured
- Cyclooxygenase 2
(genetics, metabolism)
- Cytoprotection
- Dinoprostone
(metabolism)
- Dose-Response Relationship, Drug
- Enzyme Induction
- Enzyme Inhibitors
(pharmacology)
- Heme Oxygenase-1
(antagonists & inhibitors, biosynthesis, genetics)
- Humans
- Myocytes, Cardiac
(drug effects, enzymology, pathology)
- Natriuretic Peptide, Brain
(metabolism)
- Organometallic Compounds
(metabolism, pharmacology)
- Primary Cell Culture
- RNA Interference
- Signal Transduction
(drug effects)
- Thrombin
(pharmacology)
- Time Factors
- Transfection
|