title: Nitric oxide and carbon monoxide antagonize TGF-β through ligand-independent internalization of TβR1/ALK5.
abstract: Transforming growth factor (TGF)-β plays a central role in vascular homeostasis and in the pathology of vascular disease. There is a growing appreciation for the role of nitric oxide (NO) and carbon monoxide (CO) as highly diffusible, bioactive signaling molecules in the vasculature. We hypothesized that both NO and CO increase endocytosis of TGF-β receptor type 1 (TβR1) in vascular smooth muscle cells (VSMCs) through activation of dynamin-2, shielding cells from the effects of circulating TGF-β. In this study, primary cultures of VSMCs from Sprague-Dawley rats were treated with NO-releasing molecule 3 (a NO chemical donor), CO-releasing molecule 2 (a CO chemical donor), or control. NO and CO stimulated dynamin-2 activation in VSMCs. NO and CO promoted time- and dose-dependent endocytosis of TβR1. By decreasing TβR1 surface expression through this dynamin-2-dependent process, NO and CO diminished the effects of TGF-β on VSMCs. These findings help explain an important mechanism by which NO and CO signal in the vasculature by decreasing surface expression of TβR1 and the cellular response to TGF-β.
authors.affiliation: Department of Medicine University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Michael B
authors.initials: MB
authors.lastname: Hovater
authors.affiliation: Department of Medicine University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Ying
authors.affiliation: Division of Nephrology, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine University of Alabama at Birmingham, Birmingham, Alabama; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Veterans Affairs Medical Center, Birmingham, Alabama.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Division of Nephrology, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine University of Alabama at Birmingham, Birmingham, Alabama; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; Department of Veterans Affairs Medical Center, Birmingham, Alabama psanders@uab.edu.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sanders
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D034285:Dynamin II / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D058105:Polymerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D018125:Receptors, Transforming Growth Factor beta; D020825:T-Box Domain Proteins; C540454:Tbr1 protein, rat; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D002248:Carbon Monoxide; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat; D034285:Dynamin II
keywords: activin receptor-like kinase 5; carbon monoxide; dynamin-2; nitric oxide; transforming growth factor-β; vascular smooth muscle
references.citation: DNA Cell Biol. 2002 Apr;21(4):307-21
references.pmid: 12042070
references.citation: Trends Cell Biol. 1994 May;4(5):172-8
references.pmid: 14731645
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G184-91
references.pmid: 17991708
references.citation: J Biol Chem. 1997 Dec 26;272(52):32804-9
references.pmid: 9407056
references.citation: Am J Physiol. 1998 Jul;275(1):F18-24
references.pmid: 9689000
references.citation: Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2178-84
references.pmid: 22814752
references.citation: Semin Nephrol. 2012 May;32(3):269-76
references.pmid: 22835458
references.citation: Nature. 1994 Aug 4;370(6488):341-7
references.pmid: 8047140
references.citation: Cell Res. 2009 Jan;19(1):128-39
references.pmid: 19114990
references.citation: Am J Physiol Renal Physiol. 2005 Aug;289(2):F314-21
references.pmid: 15827348
references.citation: Am J Physiol Renal Physiol. 2009 Aug;297(2):F237-43
references.pmid: 19339634
references.citation: Semin Nephrol. 2012 May;32(3):277-86
references.pmid: 22835459
references.citation: Rheumatology (Oxford). 2008 Sep;47(9):1323-8
references.pmid: 18621749
references.citation: J Cell Sci. 2009 Jun 1;122(Pt 11):1863-71
references.pmid: 19461075
references.citation: Hypertension. 2013 Nov;62(5):951-6
references.pmid: 24041947
references.citation: Br J Pharmacol. 2007 Apr;150(8):977-86
references.pmid: 17339836
references.citation: Am J Physiol Renal Physiol. 2003 Nov;285(5):F902-8
references.pmid: 12865256
references.citation: J Am Soc Nephrol. 2007 Feb;18(2):414-20
references.pmid: 17229906
references.citation: J Clin Invest. 1989 Apr;83(4):1404-8
references.pmid: 2703537
references.citation: J Biol Chem. 1969 Dec 10;244(23):6388-94
references.pmid: 4390967
references.citation: J Exp Med. 2000 Oct 2;192(7):1015-26
references.pmid: 11015442
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1295-300
references.pmid: 16432212
references.citation: J Cell Biol. 2011 Jan 10;192(1):101-10
references.pmid: 21220511
references.citation: J Biol Chem. 2001 Apr 27;276(17):14249-56
references.pmid: 11120737
references.citation: Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55
references.pmid: 4386763
references.citation: Cardiovasc Pathol. 2013 Sep-Oct;22(5):401-7
references.pmid: 23375582
references.citation: Development. 2009 Nov;136(22):3699-714
references.pmid: 19855013
references.citation: J Cell Biol. 2002 Sep 30;158(7):1239-49
references.pmid: 12356868
references.citation: J Cell Sci. 2005 Aug 15;118(Pt 16):3573-84
references.pmid: 16105881
references.citation: Curr Opin Nephrol Hypertens. 2011 Jan;20(1):37-43
references.pmid: 21088577
references.citation: Biochem Pharmacol. 1989 Apr 15;38(8):1368-70
references.pmid: 2539825
references.citation: J Vasc Res. 2003 Jan-Feb;40(1):37-46
references.pmid: 12644724
references.citation: Int J Biochem Cell Biol. 2013 Feb;45(2):201-12
references.pmid: 23041477
references.citation: Atherosclerosis. 1995 Sep;117(1):97-106
references.pmid: 8546759
references.citation: Antioxid Redox Signal. 2008 Oct;10(10):1767-812
references.pmid: 18576916
references.citation: Circ Res. 2002 Feb 8;90(2):E17-24
references.pmid: 11834719
references.citation: Bioessays. 2004 Mar;26(3):270-80
references.pmid: 14988928
references.citation: Mol Vis. 2007 Jan 24;13:66-78
references.pmid: 17277740
references.citation: J Biol Chem. 1984 Sep 10;259(17):10995-1000
references.pmid: 6088525
references.citation: J Cell Biochem. 2007 May 1;101(1):9-33
references.pmid: 17340614
references.citation: Am J Respir Cell Mol Biol. 2011 May;44(5):614-20
references.pmid: 21216973
references.citation: Circulation. 2008 Jan 15;117(2):231-41
references.pmid: 18195184
references.citation: J Cell Sci. 2007 Feb 1;120(Pt 3):492-501
references.pmid: 17251380
references.citation: Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1255-61
references.pmid: 7543000
references.citation: J Hepatol. 2011 Aug;55(2):369-78
references.pmid: 21184784
references.citation: Biomed Res Int. 2013;2013:912431
references.pmid: 24066302
references.citation: Eur J Pharmacol. 1994 May 12;257(1-2):123-30
references.pmid: 8082692
references.citation: Neurol Med Chir (Tokyo). 2003 Apr;43(4):175-80; discussion 180
references.pmid: 12760495
references.citation: Am J Physiol Renal Physiol. 2013 Mar 1;304(5):F543-52
references.pmid: 23235481
references.citation: Adv Microb Physiol. 2009;56:85-167
references.pmid: 20943125
references.citation: Am J Physiol. 1997 Mar;272(3 Pt 2):F319-24
references.pmid: 9087674
references.citation: J Biol Chem. 2000 Dec 29;275(52):40904-9
references.pmid: 11018038
references.citation: J Biol Chem. 2012 Apr 6;287(15):11677-88
references.pmid: 22351764
references.citation: Circulation. 1995 May 1;91(9):2306-9
references.pmid: 7729015
references.citation: Mol Pain. 2011 Dec 22;7:101
references.pmid: 22192148
references.citation: J Cell Physiol. 1994 May;159(2):371-8
references.pmid: 8163576
references.citation: Am J Physiol. 1999 Oct;277(4):H1293-8
references.pmid: 10516163
references.citation: Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H1-H11
references.pmid: 21498777
references.citation: J Pharmacol Exp Ther. 2007 Apr;321(1):187-94
references.pmid: 17229879
references.citation: Am J Physiol Renal Physiol. 2011 Jul;301(1):F118-24
references.pmid: 21490139
references.citation: Nitric Oxide. 2011 Apr 30;24(3):139-50
references.pmid: 21335096
references.citation: Matrix Biol. 2013 Aug 8;32(6):307-15
references.pmid: 23583521