Abstract 139: Pharmacologic Modifiers of Epigenetic Histone Methylation Attenuate Smooth Muscle Cell Proliferation, Inflammatory Activation and Dedifferentiation
Introduction: Activation and dedifferentiation of smooth muscle cells (SMCs) at sites of vascular injury is regulated by epigenetic mechanisms. Epigenetic histone methylation has been recognized as a dynamic mark controlling many biological processes in health and disease.
We assesed the hypothesis, that specific inhibitors of histone methyltransferases and demethylases effect SMC proliferation, inflammation and dedifferentiation.
Methods: We studied the effects of the following epigenetic modifiers on smooth muscle cell proliferation, MCP-1 expression and TNFα-induced dedifferentiation: chaetocin, 3-deazaneplanocin (3-DZN), AMI-1, UNC0638, 2,4-pyridinedicarboxylic acid, methylstat, daminozide and GSKJ-4.
Results: SMC proliferation was inhibited by treatment with 3-DZN, AMI-1, methylstat, chaetocin and GSK-J. TNFα-induced down regulation of SM22α expression as a marker of dedifferentiation was attenuated by treatment with UNC0638 and GSK-J4. TNFα-induced MCP-1 expression was particularly sensitive to inhibition of the histone methylation machinery, as all tested compounds with the exception of methylstat and UNC0638 caused a significant reduction of MCP-1 expression. UNC0638, chaetocin and 2,4-PDCA could attenuate TNFα-induced down regulation of SM22α expression up to 72h after the initial treatment. The sustained effect of the specific G9a histone methyltransferase inhibitor UNC0638 was associated with a strong and sustained reduction of histone h3 lysine 9 dimethylation at the SM22α promoter after 24 and 72h.
Conclusion: Our data hint at the potential of modulating specific histone methylation marks in SMCs to target SMC activation and phenotypes in vascular diseases and warrant further research to dissect histone methylation dependent mechanisms in SMCs.
Author Disclosures: F. Kahles: None. J. Marx: None. A. Makowska: None. M. Lehrke: None. N. Marx: None. H. Findeisen: None.
- © 2014 by American Heart Association, Inc.