Alcohol Inhibits Smooth Muscle Cell Proliferation Via Regulation of the Notch Signaling Pathway

Overview

Journal Arterioscler Thromb Vasc Biol

Date 2010 Oct 9

PMID 20930168

Citations 22

Authors

David Morrow

John P Cullen

Weimin Liu

Paul A Cahill

Eileen M Redmond

Affiliations

Soon will be listed here.

Abstract

Objective: To determine the role of Notch signaling in mediating alcohol's inhibition of smooth muscle cell (SMC) proliferation.

Methods And Results: Treatment of human coronary artery SMCs with ethanol (EtOH) decreased Notch 1 mRNA and Notch 1 intracellular domain protein levels, in the absence of any effect on Notch 3. EtOH treatment also decreased C-promoter binding factor-1 (CBF-1)/recombination signal-binding protein (RBP)-jk promoter activity and Notch target gene (hairy related transcription factor [HRT-1] or HRT-2) expression. These effects were concomitant with an inhibitory effect of EtOH on SMC proliferation. Overexpression of constitutively active Notch 1 intracellular domain or human hairy related transcription factor-1 (hHRT-1) prevented the EtOH-induced inhibition of SMC proliferation. In vivo, Notch 1 and HRT-1 mRNA expression was increased after ligation-induced carotid artery remodeling. The vessel remodeling response was inhibited in mice that received "moderate" amounts of alcohol by gavage daily; intimal-medial thickening was markedly reduced, and medial and neointimal SMC proliferating cell nuclear antigen expression was decreased. Moreover, Notch 1 and HRT-1 expression, induced after ligation injury, was inhibited by moderate alcohol consumption.

Conclusions: EtOH inhibits Notch signaling and, subsequently, SMC proliferation, in vitro and in vivo. The modulation of Notch signaling in SMCs by EtOH may be relevant to the cardiovascular protective effects of moderate alcohol consumption purported by epidemiological studies.

Citing Articles

Endothelial Homeostasis Under the Influence of Alcohol-Relevance to Atherosclerotic Cardiovascular Disease.

Gusti Y, Liu W, Athar F, Cahill P, Redmond E Nutrients. 2025; 17(5).

PMID: 40077672 PMC: 11901717. DOI: 10.3390/nu17050802.

Caveolin-1 inhibition mediates the opposing effects of alcohol on γ-secretase activity in arterial endothelial and smooth muscle cells.

Rajendran N, Liu W, Cahill P, Redmond E Physiol Rep. 2023; 11(1):e15544.

PMID: 36635975 PMC: 9837422. DOI: 10.14814/phy2.15544.

Vascular smooth muscle cell dysfunction in neurodegeneration.

Hayes G, Pinto J, Sparks S, Wang C, Suri S, Bulte D Front Neurosci. 2022; 16:1010164.

PMID: 36440263 PMC: 9684644. DOI: 10.3389/fnins.2022.1010164.

Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome.

Jespersen K, Li C, Batra R, Stephenson C, Harding P, Sestak K J Immunol Res. 2022; 2022:7538649.

PMID: 35211631 PMC: 8863478. DOI: 10.1155/2022/7538649.

Moderate dose alcohol protects against serum amyloid protein A1-induced endothelial dysfunction via both notch-dependent and notch-independent pathways.

Rajendran N, Liu W, Chu C, Cahill P, Redmond E Alcohol Clin Exp Res. 2021; 45(11):2217-2230.

PMID: 34585422 PMC: 8642281. DOI: 10.1111/acer.14706.

References

Lai E . Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins. EMBO Rep. 2002; 3(9):840-5. PMC: 1084223. DOI: 10.1093/embo-reports/kvf170. View

Klatsky A, Armstrong M, Friedman G . Alcohol and mortality. Ann Intern Med. 1992; 117(8):646-54. DOI: 10.7326/0003-4819-117-8-646. View

Li Y, Takeshita K, Liu P, Satoh M, Oyama N, Mukai Y . Smooth muscle Notch1 mediates neointimal formation after vascular injury. Circulation. 2009; 119(20):2686-92. PMC: 2744039. DOI: 10.1161/CIRCULATIONAHA.108.790485. View

Mukamal K, Chen C, Rao S, Breslow R . Alcohol consumption and cardiovascular mortality among U.S. adults, 1987 to 2002. J Am Coll Cardiol. 2010; 55(13):1328-35. PMC: 3865979. DOI: 10.1016/j.jacc.2009.10.056. View

Morrow D, Cullen J, Cahill P, Redmond E . Cyclic strain regulates the Notch/CBF-1 signaling pathway in endothelial cells: role in angiogenic activity. Arterioscler Thromb Vasc Biol. 2007; 27(6):1289-96. DOI: 10.1161/ATVBAHA.107.142778. View

Sweeney C, Morrow D, Birney Y, Coyle S, Hennessy C, Scheller A . Notch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migration via a CBF-1/RBP-Jk dependent pathway. FASEB J. 2004; 18(12):1421-3. DOI: 10.1096/fj.04-1700fje. View

Sayeed S, Cullen J, Coppage M, Sitzmann J, Redmond E . Ethanol differentially modulates the expression and activity of cell cycle regulatory proteins in rat aortic smooth muscle cells. Eur J Pharmacol. 2002; 445(3):163-70. DOI: 10.1016/s0014-2999(02)01761-2. View

Merritt R, Guruge B, Miller D, Chaitman B, Bora P . Moderate alcohol feeding attenuates postinjury vascular cell proliferation in rabbit angioplasty model. J Cardiovasc Pharmacol. 1997; 30(1):19-25. DOI: 10.1097/00005344-199707000-00004. View

Liu M, Lin S, Chen Y . Local alcohol delivery may reduce phenotype conversion of smooth muscle cells and neointimal formation in rabbit iliac arteries after balloon injury. Atherosclerosis. 1996; 127(2):221-7. DOI: 10.1016/s0021-9150(96)05959-x. View

10.

Hendrickson R, Cahill P, Sitzmann J, Redmond E . Ethanol enhances basal and flow-stimulated nitric oxide synthase activity in vitro by activating an inhibitory guanine nucleotide binding protein. J Pharmacol Exp Ther. 1999; 289(3):1293-300. View

11.

Hendrickson R, Cahill P, Mckillop I, Sitzmann J, Redmond E . Ethanol inhibits mitogen activated protein kinase activity and growth of vascular smooth muscle cells in vitro. Eur J Pharmacol. 1999; 362(2-3):251-9. DOI: 10.1016/s0014-2999(98)00771-7. View

12.

Schweisguth F . Regulation of notch signaling activity. Curr Biol. 2004; 14(3):R129-38. View

13.

Costanzo S, Di Castelnuovo A, Donati M, Iacoviello L, de Gaetano G . Alcohol consumption and mortality in patients with cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2010; 55(13):1339-47. DOI: 10.1016/j.jacc.2010.01.006. View

14.

Thun M, Peto R, Lopez A, Monaco J, Henley S, Heath Jr C . Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med. 1997; 337(24):1705-14. DOI: 10.1056/NEJM199712113372401. View

15.

Morrow D, Sweeney C, Birney Y, Cummins P, Walls D, Redmond E . Cyclic strain inhibits Notch receptor signaling in vascular smooth muscle cells in vitro. Circ Res. 2005; 96(5):567-75. DOI: 10.1161/01.RES.0000159182.98874.43. View

16.

Shawber C, Kitajewski J . Notch function in the vasculature: insights from zebrafish, mouse and man. Bioessays. 2004; 26(3):225-34. DOI: 10.1002/bies.20004. View

17.

Morrow D, Cullen J, Liu W, Guha S, Sweeney C, Birney Y . Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A. Arterioscler Thromb Vasc Biol. 2009; 29(7):1112-8. PMC: 2794048. DOI: 10.1161/ATVBAHA.109.186890. View

18.

Klatsky A . Alcohol and cardiovascular health. Physiol Behav. 2010; 100(1):76-81. DOI: 10.1016/j.physbeh.2009.12.019. View

19.

Doi H, Iso T, Yamazaki M, Akiyama H, Kanai H, Sato H . HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. Arterioscler Thromb Vasc Biol. 2005; 25(11):2328-34. DOI: 10.1161/01.ATV.0000185829.47163.32. View

20.

Korshunov V, Berk B . Flow-induced vascular remodeling in the mouse: a model for carotid intima-media thickening. Arterioscler Thromb Vasc Biol. 2003; 23(12):2185-91. DOI: 10.1161/01.ATV.0000103120.06092.14. View