Intraluminal delivery of thrombospondin-2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model.
In an effort to inhibit the response to vascular injury that leads to intimal hyperplasia, this study investigated the in vivo efficacy of intraluminal delivery of thrombospondin-2 (TSP-2) small interfering RNA (siRNA). Common carotid artery (CCA) balloon angioplasty injury was performed in rats. Immediately after denudation, CCA was transfected intraluminally (15 min) with one of the following: polyethylenimine (PEI)+TSP-2 siRNA, saline, PEI only, or PEI+control siRNA. CCA was analyzed at 24 h or 21 d by using quantitative real-time PCR and immunohistochemistry. TSP-2 gene and protein expression were significantly up-regulated after endothelial denudation at 24 h and 21 d compared with contralateral untreated, nondenuded CCA. Treatment with PEI+TSP-2 siRNA significantly suppressed TSP-2 gene expression (3.1-fold) at 24 h and TSP-2 protein expression, cell proliferation, and collagen deposition up to 21 d. These changes could be attributed to changes in TGF-β and matrix metalloproteinase-9, the downstream effectors of TSP-2. TSP-2 knockdown induced anti-inflammatory M2 macrophage polarization at 21 d; however, it did not significantly affect intima/media ratios. In summary, these data demonstrate effective siRNA transfection of the injured arterial wall and provide a clinically effective and translationally applicable therapeutic strategy that involves nonviral siRNA delivery to ameliorate the response to vascular injury.-Bodewes, T. C. F., Johnson, J. M., Auster, M., Huynh, C., Muralidharan, S., Contreras, M., LoGerfo, F. W., Pradhan-Nabzdyk, L. Intraluminal delivery of thrombospondin-2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model.
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.|Department of Vascular Surgery, University Medical Center, Utrecht, The Netherlands; and.
Thomas C F
TC
Bodewes
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Joel M
JM
Johnson
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Michael
M
Auster
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.|Department of Surgery, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA.
Cindy
C
Huynh
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Sriya
S
Muralidharan
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Mauricio
M
Contreras
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Frank W
FW
LoGerfo
Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; lpradhan@bidmc.harvard.edu.
Leena
L
Pradhan-Nabzdyk
D000800:Angioplasty, Balloon; D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism*; D049109:Cell Proliferation; D003094:Collagen; D005786:Gene Expression Regulation / Q000502:physiology*; D008264:Macrophages; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D051381:Rats; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000099262:Thrombospondin 2
D003094:Collagen; D020780:Matrix Metalloproteinase 9; D034741:RNA, Small Interfering; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D000099262:Thrombospondin 2
arterial injury; extracellular matrix protein; intimal hyperplasia; siRNA; vascular remodeling
Sci China Life Sci. 2015 Jul;58(7):674-81
25921940
Mol Cell Biol. 2003 Aug;23(15):5401-8
12861025
Gene Ther. 2012 Jun;19(6):630-6
22456326
J Vasc Surg. 2010 May;51(5 Suppl):5S-17S
20435258
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1510-20
12907463
Eur J Vasc Endovasc Surg. 2011 Sep;42 Suppl 1:S19-29
21855014
Circulation. 1998 Nov 17;98(20):2195-201
9815875
J Histochem Cytochem. 2009 Apr;57(4):301-13
19029404
J Clin Invest. 2001 Apr;107(8):929-34
11306593
Am J Pathol. 2005 Jul;167(1):81-8
15972954
Ann Vasc Surg. 2013 Nov;27(8):1134-45
24011814
Diabetes. 2016 Jul;65(7):2006-19
27207516
PLoS One. 2012;7(6):e39123
22720046
J Am Coll Surg. 2007 Mar;204(3):399-408
17324773
Am J Pathol. 2008 Sep;173(3):879-91
18688033
Circ Res. 2002 Nov 1;91(9):845-51
12411400
J Vasc Surg. 2012 Aug;56(2):446-54
22521802
J Pathol. 2013 Jan;229(2):176-85
23096265
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
10708953
J Vasc Surg. 2006 Apr;43(4):742-751; discussion 751
16616230
Proc Natl Acad Sci U S A. 1986 Dec;83(23):9050-4
3491367
Circulation. 2004 Aug 24;110(8):940-7
15302784
J Vasc Surg. 2010 Dec;52(6):1608-15
20801607
J Surg Res. 2011 May 15;167(2):287-97
21324395
Circ Res. 2008 Aug 15;103(4):378-87
18617696
BMC Genomics. 2016 Jan 05;17 :20
26728506
J Cell Biol. 1998 Jan 26;140(2):419-30
9442117
Biochim Biophys Acta. 2014 Aug;1840(8):2396-402
24440155
Cell Biochem Biophys. 2012 Jan;62(1):125-35
21850543
J Invest Dermatol. 1999 Nov;113(5):782-7
10571734
Nat Chem Biol. 2006 Dec;2(12):711-9
17108989
Circulation. 2015 Jan 27;131(4):e29-322
25520374
PLoS One. 2014 Jun 02;9(6):e98904
24887332
Biochem Biophys Res Commun. 2015 Sep 4;464(4):1022-7
26168731
FASEB J. 2009 Feb;23(2):557-64
18940893
Biomaterials. 2011 Mar;32(9):2388-98
21183213
Circ Res. 1996 Sep;79(3):541-50
8781487
J Am Coll Surg. 2011 Nov;213(5):668-76
21840228