title: Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension.
abstract: Smad7 has been shown to negatively regulate fibrosis and inflammation, but its role in angiotensin II (Ang II)-induced hypertensive cardiac remodeling remains unknown. Therefore, the present study investigated the role of Smad7 in hypertensive cardiopathy induced by angiotensin II infusion. Hypertensive cardiac disease was induced in Smad7 gene knockout (KO) and wild-type (WT) mice by subcutaneous infusion of Ang II (1.46 mg/kg/day) for 28 days. Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impairing cardiac function including a significant increase in left ventricular (LV) mass (P<0.01),reduction of LV ejection fraction(P<0.001) and fractional shortening(P<0.001). Real-time PCR, Western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, interleukin-1β, TNF-α, and infiltration of CD3(+) T cells and F4/80(+) macrophages. Further studies revealed that enhanced activation of the Sp1-TGFβ/Smad3-NF-κB pathways and downregulation of miR-29 were mechanisms though which deletion of Smad7 promoted Ang II-mediated cardiac remodeling. In conclusions, Smad7 plays a protective role in AngII-mediated cardiac remodeling via mechanisms involving the Sp1-TGF-β/Smad3-NF.κB-miR-29 regulatory network.
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Li Hua
authors.initials: LH
authors.lastname: Wei
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: You Qi
authors.initials: YQ
authors.lastname: Li
authors.forename: Hai-yong
authors.initials: HY
authors.lastname: Chen
authors.forename: Rainer
authors.initials: R
authors.lastname: Heuchel
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Yan
authors.forename: Cheuk-Man
authors.initials: CM
authors.lastname: Yu
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology; D006973:Hypertension / Q000473:pathology* / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D000804:Angiotensin II
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C82-97
references.pmid: 16870827
references.citation: Circulation. 2007 Nov 6;116(19):2127-38
references.pmid: 17967775
references.citation: Mol Ther. 2012 Jun;20(6):1251-60
references.pmid: 22395530
references.citation: Am J Physiol Renal Physiol. 2007 Sep;293(3):F885-94
references.pmid: 17567933
references.citation: Am J Pathol. 2005 Mar;166(3):761-71
references.pmid: 15743788
references.citation: Circ Res. 2010 Jun 11;106(11):1675-80
references.pmid: 20538689
references.citation: Mol Cell Biol. 1994 Oct;14(10):6570-83
references.pmid: 7935378
references.citation: Mol Cell. 2000 Dec;6(6):1365-75
references.pmid: 11163210
references.citation: J Am Soc Nephrol. 2010 Sep;21(9):1477-87
references.pmid: 20595680
references.citation: Circ Res. 2011 Jan 21;108(2):164-75
references.pmid: 21127293
references.citation: J Hypertens. 2010 Sep;28 Suppl 1:S25-32
references.pmid: 20823713
references.citation: Biochim Biophys Acta. 2001 Dec 30;1522(3):195-206
references.pmid: 11779634
references.citation: Nephrol Dial Transplant. 2009 May;24(5):1443-54
references.pmid: 19096081
references.citation: J Am Soc Nephrol. 2003 Jun;14(6):1535-48
references.pmid: 12761254
references.citation: J Histochem Cytochem. 1995 Jan;43(1):97-102
references.pmid: 7822770
references.citation: Am J Physiol Renal Physiol. 2012 Apr 15;302(8):F986-97
references.pmid: 22237801
references.citation: Hypertension. 2000 Jan;35(1 Pt 2):193-201
references.pmid: 10642297
references.citation: Kidney Int Suppl. 2005 Apr;(94):S83-91
references.pmid: 15752249
references.citation: Hypertension. 2010 May;55(5):1165-71
references.pmid: 20231525
references.citation: Biochem J. 2000 Jul 15;349(Pt 2):435-41
references.pmid: 10880342
references.citation: Circ Res. 2002 Nov 29;91(11):988-98
references.pmid: 12456484
references.citation: Hypertension. 2009 Oct;54(4):877-84
references.pmid: 19667256
references.citation: Front Biosci (Landmark Ed). 2012 Jan 01;17:221-31
references.pmid: 22201740
references.citation: Cancer Cell. 2010 Apr 13;17(4):333-47
references.pmid: 20385359
references.citation: J Am Soc Nephrol. 2005 May;16(5):1371-83
references.pmid: 15788474
references.citation: J Pathol. 2010 Aug;221(4):390-401
references.pmid: 20593491
references.citation: Diabetes. 2011 Feb;60(2):590-601
references.pmid: 20980457
references.citation: J Am Soc Nephrol. 2011 Aug;22(8):1462-74
references.pmid: 21784902
references.citation: Circulation. 2011 Jan 25;123(3):327-34
references.pmid: 21263005
references.citation: Circulation. 2005 May 17;111(19):2509-17
references.pmid: 15883213
references.citation: Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1685-96
references.pmid: 11959632
references.citation: J Immunol. 2006 Jun 1;176(11):6777-84
references.pmid: 16709837
references.citation: Circ Res. 2006 Apr 28;98(8):1032-9
references.pmid: 16556868
references.citation: Cancer Cell. 2008 Nov 4;14(5):369-81
references.pmid: 18977326
references.citation: J Biol Chem. 2001 Mar 9;276(10):6983-92
references.pmid: 11114293
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32
references.pmid: 18723672