Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of HIF-1alpha, SDF-1alpha and VEGF-B.

Abstract

Heme oxygenase-1 (HO-1), a known cytoprotective enzyme implicated also in the cell cycle regulation and angiogenesis, exerts many of its beneficial effects through carbon monoxide (CO). We studied the roles of HO-1 and CO in cardiac regeneration after myocardial infarction. Prior to coronary artery ligation, male Wistar rats were given either cobolt protoporphyrin IX to induce HO-1 or CO-donor methylene chloride. Cardiac regeneration was assessed by immunohistochemistry and confocal microscopy. CO significantly increased the accumulation of c-kit+ stem/progenitor cells into the infarct area and induced formation of new coronary arteries by promoting a substantial differentiation of c-kit+ cells into vascular smooth muscle cells (c-kit+/GATA6+ cells). Furthermore, CO increased proliferation of cardiomyocytes in the infarct border area at 4weeks post-infarction. This suggests proliferation of newly formed cardiomyocytes derived from c-kit+ cells as 10% of c-kit+ cells expressed early cardiac marker Nkx2.5. Increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha), stromal cell derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor-B (VEGF-B) were found in the infarct areas of CO-donor pretreated hearts suggesting that these factors potentially promoted the migration of c-kit+ cells into the infarct area and subsequent vasculogenesis and myocardial regeneration by CO. HO-1 increased both capillary and vascular densities, while only a small increase of c-kit+ cells was found. HO-1 upregulated SDF-1alpha, but did not have effect on HIF-1alpha and VEGF-B. In conclusion, HO-1 and CO have differential roles and mechanisms of action in cardiac regeneration. Modulation of the HO-1/CO axis may provide a novel tool for the repair of cardiac injury.

• Authors: Päivi Lakkisto, Ville Kytö, Hanna Forsten, Juha-Matti Siren, Heli Segersvärd, Liisa-Maria Voipio-Pulkki, Mika Laine, Kari Pulkki, Ilkka Tikkanen
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 635 Issue 1-3 Pg. 156-64 (Jun 10 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20303947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• Vascular Endothelial Growth Factor B
• Carbon Monoxide
• Carboxyhemoglobin
• Heme Oxygenase-1
• Proto-Oncogene Proteins c-kit

Topics

• Animals
• Body Weight (drug effects)
• Carbon Monoxide (metabolism)
• Carboxyhemoglobin (genetics, metabolism)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Chemokine CXCL12 (metabolism)
• Enzyme Induction (drug effects)
• Gene Expression Regulation
• Heme Oxygenase-1 (biosynthesis, genetics, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Muscle, Smooth, Vascular (drug effects, pathology)
• Myocardial Infarction (metabolism, pathology, physiopathology)
• Myocytes, Cardiac (drug effects, pathology)
• Neovascularization, Physiologic (drug effects)
• Organ Size (drug effects)
• Proto-Oncogene Proteins c-kit (metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Wistar
• Stem Cells (drug effects, pathology)
• Time Factors
• Vascular Endothelial Growth Factor B (metabolism)