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

Lakkisto, Päivi; Kytö, Ville; Forsten, Hanna; Siren, Juha-Matti; Segersvärd, Heli; Voipio‐Pulkki, Liisa‐Maria; Laine, Mika; Pulkki, Kari; Tikkanen, Ilkka

doi:10.1016/j.ejphar.2010.02.050

Cited by 68 publications

(79 citation statements)

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“…However, eukaryotic organisms use endogenous CO, produced during heme degradation by the highly conserved HO enzymes [2][3][4]12,26,27], as a neurotransmitter and as a physiological signal molecule [12,21,152]. Moreover, diverse microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth [10,11,22].…”

Section: Discussionmentioning

confidence: 99%

“…CO has been also shown to regulate cell cycle, indeed it decreases proliferation of VSMC, of airway SMC, and of pancreatic stellate cells, while it increases proliferation of EC [152]. Indeed, CO may specifically contribute to the re-endothelialization of the vessel wall at sites of vascular injury inducing the production of angiogenic mediators [e.g., VEGF, IL-8, and stromal cell derived factor-1 (SDF-1)] and decreasing the levels of the anti-angiogenic mediators [e.g., VEGF receptor 1 and soluble endoglin (sEng)].…”

Section: Co Signalingmentioning

confidence: 99%

“…In contrast, HO-1 induces angiogenesis presumably by a CO-independent mechanism, as HO-1 increases the expression of SDF-1a only. Thus, modulation of the HO-1/CO axis may provide a novel tool for the repair of cardiac injury [152] (Fig. 2).…”

Section: Co Signalingmentioning

confidence: 99%

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CO metabolism, sensing, and signaling

et al. 2011

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Abstract.CO is a colorless and odorless gas produced by the incomplete combustion of hydrocarbons, both of natural and anthropogenic origin. Several microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth. On the other hand, eukaryotic organisms use endogenous CO, produced during heme degradation, as a neurotransmitter and as a signal molecule. CO sensors act as signal transducers by coupling a ''regulatory'' heme-binding domain to a ''functional'' signal transmitter. Although high CO concentrations inhibit generally heme-protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogenactivated protein kinases. This review summarizes recent insights into CO metabolism, sensing, and signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Co Signalingmentioning

confidence: 99%

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CO metabolism, sensing, and signaling

et al. 2011

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“…[9][10][11][12][13] Recently, studies from our group and others also demonstrated that HO-1 promotes neovascularization in ischemic heart. [14][15][16] HO-1 and CO can induce the expressions of vascular endothelial growth factor and SDF-1α, which then promote the recruitment of circulating stem/progenitor cells for neovascularization. 14,15 Nonetheless, the molecular mechanism underlying the regulation of SDF-1α gene expression by HO-1/ CO remains elusive.…”

mentioning

confidence: 99%

“…[14][15][16] HO-1 and CO can induce the expressions of vascular endothelial growth factor and SDF-1α, which then promote the recruitment of circulating stem/progenitor cells for neovascularization. 14,15 Nonetheless, the molecular mechanism underlying the regulation of SDF-1α gene expression by HO-1/ CO remains elusive. To this end, here we performed the in vitro experiments to investigate the signaling pathway and the downstream transcriptional factor responsible for CO-induced SDF-1α gene expression in primary cardiomyocytes and H9C2 cardiomyoblasts.…”

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confidence: 99%

Activator Protein-2α Mediates Carbon Monoxide–Induced Stromal Cell–Derived Factor-1α Expression and Vascularization in Ischemic Heart

Lin

Chen

Chiang

et al. 2013

ATVB

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Objective-Increased cardiac stromal cell-derived factor-1α (SDF-1α) expression promotes neovascularization and myocardial repair after ischemic injury through recruiting stem cells and reducing cardiomyocyte death. Previous studies have shown that heme oxygenase-1 and its reaction byproduct, carbon monoxide (CO), induce SDF-1α expression in ischemic heart. However, the mechanism underlying heme oxygenase-1/CO-induced cardiac SDF-1α expression remains elusive. This study aims to investigate the signaling pathway and the transcriptional factor that mediate CO-induced SDF-1α gene expression and cardioprotection. Approach and Results-CO gas and a CO-releasing compound, tricarbonyldichlororuthenium (II) dimer, dosedependently induced SDF-1α expression in primary neonatal cardiomyocytes and H9C2 cardiomyoblasts. Promoter luciferase-reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation demonstrated that the activator protein 2α (AP-2α) mediated tricarbonyldichlororuthenium (II) dimer-induced SDF-1α gene transcription. Tricarbonyldichlororuthenium (II) dimer induced AP-2α expression via protein kinase B (AKT)-dependent signaling.AKT inhibition or AP-2α knockdown reduced tricarbonyldichlororuthenium (II) dimer-induced SDF-1α expression. Coronary ligation induced transient increases of cardiac AP-2α and SDF-1α expression, which were declined at 1 week postinfarction in mice. Periodic exposure of coronary-ligated mice to CO (250 ppm for 1 hour/day, 6 days) resumed the induction of AP-2α and SDF-1α gene expression in infarcted hearts. Immunohistochemistry and echocardiography performed at 4 weeks after coronary ligation revealed that CO treatment enhanced neovascularization in the myocardium of peri-infarct region and improved cardiac function. CO-mediated SDF-1α expression and cardioprotection was ablated by intramyocardial injection of lentivirus bearing specific short hairpin RNA targeting AP-2α. Conclusions-Our data demonstrate that AKT-dependent upregulation of AP-2α is essential for CO-induced SDF-1α expression and myocardial repair after ischemic injury. (Arterioscler Thromb Vasc Biol. 2013;33:785-794.) Key Words: activator protein 2α ◼ carbon monoxide ◼ heme oxygenase-1 ◼ ischemic heart ◼ stromal cell-derived factor-1α ◼ vascularization Activator Protein-2α Mediates Carbon MonoxideInduced Stromal Cell-Derived Factor-1α Expression and Vascularization in Ischemic HeartHeng-Huei Lin, Yen-Hui Chen, Ming-Tsai Chiang, Pei-Ling Huang, Lee-Young Chau Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results HO-1/CO Induces SDF-1α ExpressionTo confirm our previous finding that HO-1 overexpression promotes SDF-1α gene induction in myocardium in vivo, 14 we performed HO-1 gene transduction experiment in primary neonatal cardiomyocytes and H9C2 cardiomyoblasts. As shown in Figure 1A and 1B, when cells were infected with adenovirus bearing HO-1 gene for 48 hours, SDF-1α gene expression examined by quantitative real-time PCR was significantly higher, as comp...

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Molecular Mechanisms of Actions for CO

2022

Carbon Monoxide in Drug Discovery

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

Cited by 68 publications

References 53 publications

CO metabolism, sensing, and signaling

CO metabolism, sensing, and signaling

Activator Protein-2α Mediates Carbon Monoxide–Induced Stromal Cell–Derived Factor-1α Expression and Vascularization in Ischemic Heart

Molecular Mechanisms of Actions for CO

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