Carbon monoxide induces chromatin remodelling to facilitate endothelial cell migration

Summary

Vascular injury to vessel endothelial cells (EC), caused by either mechanical damage or chronic inflammation, is still awaiting effective therapies. In the present study we hypothesised that carbon monoxide (CO) acts on the nuclear receptor Rev-erbα to induce chromatin modification and endothelial cell migration. We demonstrate that administration of low, safe doses of exogenous CO enhances endothelial cell (EC) migration, which occurs in part through chromatin remodelling and histone H3 acetylation. Further, we show that the effects of CO are dependent on inhibition of phosphorylation of glycogen synthase kinase-3 β (GSK3β), activation of haem synthesis, and increased expression of Rev-erbα. Rev-erbα is a haem-containing transcription factor which in response to CO binds to target DNA, recruits the Histone Deacetylase/nuclear Receptor Corepressor (HDAC/N-CoR) complex, and regulates transcription of genes responsible for endothelial cell migration and angiogenesis. Decreased levels of Rev-erbα in chimeric mice after bone marrow transplant from Rev-erbα following bone marrow transplantation from rev-erb^+/− mice resulted in loss of protective effects of CO against neointima formation after wire injury. Collectively, CO modifies chromatin structure through enhanced acetylation of histone H3 via a GSK3β-Rev-erbα-mediated pathway to increase EC migration. We propose that CO enhances vessel repair following injury in part by regulating EPC/EC motility via Rev-erbα. Thus, inhaled CO may be beneficial in the treatment of vascular syndromes associated with dysregulated thrombosis, wound healing, and angiogenesis.

Keywords

Carbon monoxide - vascular repair - migration - nuclear receptor

• References

• 1 Fisher M. Injuries to the vascular endothelium: vascular wall and endothelial dysfunction. Rev Neurol Dis 2008; 05 (Suppl. 01) S4-11.
• 2 McQuaid KE, Keenan AK. Endothelial barrier dysfunction and oxidative stress: roles for nitric oxide?. Exp Physiol 1997; 82: 369-376.
• 3 Wegiel B, Gallo DJ, Raman KG. et al. Nitric oxide-dependent bone marrow progenitor mobilisation by carbon monoxide enhances endothelial repair after vascular injury. Circulation 2010; 121: 537-548.
• 4 Dimmeler S, Zeiher AM. Nitric oxide-an endothelial cell survival factor. Cell death and differentiation 1999; 06: 964-968.
• 5 Naik JS, O’Donaughy TL, Walker BR. Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation. Am J Physiol Heart Circ Physiol 2003; 284: H838-845.
• 6 Schafer A, Bauersachs J. Endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation in diabetes and atherosclerosis. Curr Vasc Pharmacol 2008; 06: 52-60.
• 7 Wegiel B, Hanto DW, Otterbein LE. The social network of carbon monoxide in medicine. Trends Mol Med 2013; 19: 3-11.
• 8 Soares MP, Bach FH. Heme oxygenase-1: from biology to therapeutic potential. Trends in molecular medicine 2009; 15: 50-58.
• 9 Otterbein LE, Zuckerbraun BS, Haga M. et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nature Med 2003; 09: 183-190.
• 10 Tenhunen R. The enzymatic degradation of heme. Semin Hematol 1972; 09: 19-29.
• 11 Tenhunen R, Marver H, Pimstone NR. et al. Enzymatic degradation of heme. Oxygenative cleavage requiring cytochrome P-450. Biochemistry 1972; 11: 1716-1720.
• 12 Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase. Characterisation of the enzyme. J Biol Chem 1969; 244: 6388-6394.
• 13 Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 1968; 61: 748-755.
• 14 Dulak J, Jâozkowicz A. Carbon monoxide -- a “new” gaseous modulator of gene expression. Acta Biochim Pol 2003; 50: 31-47.
• 15 Jozkowicz A, Huk I, Nigisch A. et al. Heme oxygenase and angiogenic activity of endothelial cells: stimulation by carbon monoxide and inhibition by tin proto-porphyrin-IX. Antiox Redox Signal 2003; 05: 155-162.
• 16 Balla J, Vercellotti GM, Jeney V. et al. Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment. Antiox Redox Signal 2007; 09: 2119-2137.
• 17 Wu BJ, Midwinter RG, Cassano C. et al. Heme oxygenase-1 increases endothelial progenitor cells. Arterioscl Thromb Vasc Biol 2009; 29: 1537-1542.
• 18 Yin L, Wu N, Curtin JC. et al. Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 2007; 318: 1786-1789.
• 19 Yin L, Wu N, Lazar MA. Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal 2010; 08: e001.
• 20 Pardee KI, Xu X, Reinking J. et al. The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. PLoS Biol 2009; 07: e43.
• 21 Guenther MG, Barak O, Lazar MA. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol 2001; 21: 6091-6101.
• 22 You SH, Liao X, Weiss RE. et al. The interaction between nuclear receptor corepressor and histone deacetylase 3 regulates both positive and negative thyroid hormone action in vivo. Mol Endocrinol 2010; 24: 1359-1367.
• 23 Alenghat T, Meyers K, Mullican SE. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 2008; 456: 997-1000.
• 24 Wu N, Yin L, Hanniman EA. et al. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha. Genes Dev 2009; 23: 2201-2209.
• 25 Yin L, Wang J, Klein PS. et al. Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science 2006; 311: 1002-1005.
• 26 Hibbert B, Ma X, Pourdjabbar A. et al. Inhibition of endothelial progenitor cell glycogen synthase kinase-3beta results in attenuated neointima formation and enhanced re-endothelialisation after arterial injury. Cardiovasc Res 2009; 83: 16-23.
• 27 Yin L, Lazar MA. The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol Endocrinol 2005; 19: 1452-1459.
• 28 Lee CW, Lin WN, Lin CC. et al. Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and histone acetylation. J Cell Physiol 2006; 207: 174-186.
• 29 Inoue K, Kobayashi M, Yano K. et al. Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression. Arterioscler Thromb Vasc Biol 2006; 26: 2652-2659.
• 30 Ellis L, Hammers H, Pili R. Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer letters 2009; 280: 145-153.
• 31 Jin G, Bausch D, Knightly T. et al. Histone deacetylase inhibitors enhance endothelial cell sprouting angiogenesis in vitro. Surgery 2011; 150: 429-435.
• 32 Lin KT, Wang YW, Chen CT. et al. HDAC inhibitors augmented cell migration and metastasis through induction of PKCs leading to identification of low toxicity modalities for combination cancer therapy. Clin Cancer Res 2012; 18: 4691-4701.
• 33 Wang J, Yin L, Lazar MA. The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. J Biol Chem 2006; 281: 33842-33848.
• 34 Fujita T, Toda K, Karimova A. et al. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Nat Med 2001; 07: 598-604.
• 35 Nor JE, Mitra RS, Sutorik MM. et al. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res 2000; 37: 209-218.
• 36 Sarkar AJ, Chaturvedi K, Chen CP. et al. Changes in thrombospondin-1 levels in the endothelial cells of the anterior pituitary during estrogen-induced prolactinsecreting pituitary tumors. J Endocrinol 2007; 192: 395-403.