title: Smad7 inhibits angiotensin II-induced hypertensive cardiac remodelling.
abstract: OBJECTIVE
  Smad7 plays a negative regulatory role in many inflammatory diseases, but its effect on hypertensive disease remains unknown. The present study tested the hypothesis that overexpression of Smad7 may have therapeutic potential for angiotensin II (Ang II)-mediated hypertensive cardiac remodelling.
  
  
  RESULTS
  Hypertensive heart disease was induced in mice by subcutaneous infusion of Ang II for 28 days and treated with Smad7 by a non-invasive ultrasound-microbubble-mediated inducible Smad7 gene transfer. We found that cardiac Smad7 was largely reduced in the hypertensive heart and overexpression of cardiac Smad7 protected against the fall in the left ventricular (LV) ejection fraction (EF), an increase in LV mass, and cardiac inflammation and fibrosis such as up-regulation of pro-inflammatory cytokines (IL-1β, TNF-α) and fibrotic markers (collagen I, α-SMA), and infiltration of CD3(+) T cells and F4/80(+) macrophages. Further studies revealed that inactivation of the Sp1-TGF-β/Smad3-NF-κB (NF-κB, nuclear factor κB) pathways and prevention of cardiac miR-29 loss were mechanisms by which overexpression of Smad7 inhibited Ang II-mediated cardiac remodelling. Importantly, we also found that treatment with Smad7 when hypertensive cardiopathy established at day 14 halted the progression of cardiac injury by blunting the fall of EF and an increase in LV mass, and blocking TGF-β/Smad3-mediated cardiac fibrosis and NF-κB-driven inflammation.
  
  
  CONCLUSIONS
  Smad7 plays a protective role in Ang II-induced cardiac remodelling via mechanisms involving the Sp1-TGF-β/Smad-NF-κB-miR-29 regulatory network. Thus, Smad7 may be a novel therapeutic agent for hypertensive cardiovascular diseases.
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, 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: 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 / Q000494:pharmacology*; D000818:Animals; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000032:analysis; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D051906:Smad7 Protein / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D020257:Ventricular Remodeling
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; D000804:Angiotensin II
keywords: Ang II; Fibrosis; Inflammation; Smad7; miR-29