PMID- 32953930
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 18
DP  - 2020 Sep 11
TI  - Treatment of Hypertensive Heart Disease by Targeting Smad3 Signaling in Mice.
PG  - 791-802
LID - 10.1016/j.omtm.2020.08.003 [doi]
AB  - Transforming growth factor beta (TGF-beta)/Smad3 signaling plays a central role in 
      chronic heart disease. Here, we report that targeting Smad3 with a Smad3 
      inhibitor SIS3 in an established mouse model of hypertension significantly 
      improved cardiac dysfunctions by preserving the left ventricle (LV) ejection 
      fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. 
      In addition, SIS3 treatment also halted the progression of myocardial fibrosis by 
      blocking alpha-smooth muscle actin-positive (alpha-SMA(+)) myofibroblasts and collagen 
      matrix accumulation, and inhibited cardiac inflammation by suppressing 
      interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic 
      protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and 
      infiltration of CD3(+) T cells and F4/80(+) macrophages. Interestingly, treatment 
      with SIS3 did not alter levels of high blood pressure, revealing a blood 
      pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment 
      with SIS3 not only directly inactivated TGF-beta/Smad3 signaling but also protected 
      cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because 
      Smad7 functions as an inhibitor for both TGF-beta/Smad and nuclear factor kappaB (NF-kappaB) 
      signaling, increased cardiac Smad7 could be another mechanism through which SIS3 
      treatment blocked Smad3-mediated myocardial fibrosis and NF-kappaB-driven cardiac 
      inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart 
      disease. Results from this study demonstrate that targeting Smad3 signaling with 
      SIS3 may be a novel and effective therapy for chronic heart disease.
CI  - (c) 2020 The Authors.
FAU - Meng, Jinxiu
AU  - Meng J
AD  - Guangdong Provincial Key Laboratory of Coronary Heart Disease, Guangdong 
      Cardiovascular Institute, Guangdong Provincial People's Hospital and Guangdong 
      Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
AD  - Department of Medicine and Therapeutics, Li Ka Shing Institute of Health 
      Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese 
      University of Hong Kong, Hong Kong, China.
FAU - Qin, Yuyan
AU  - Qin Y
AD  - Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key 
      Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth 
      Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, 
      China.
AD  - Department of Medicine and Therapeutics, Li Ka Shing Institute of Health 
      Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese 
      University of Hong Kong, Hong Kong, China.
FAU - Chen, Junzhe
AU  - Chen J
AD  - Department of Medicine and Therapeutics, Li Ka Shing Institute of Health 
      Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese 
      University of Hong Kong, Hong Kong, China.
FAU - Wei, Lihua
AU  - Wei L
AD  - Department of Medicine and Therapeutics, Li Ka Shing Institute of Health 
      Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese 
      University of Hong Kong, Hong Kong, China.
FAU - Huang, Xiao-Ru
AU  - Huang XR
AD  - Guangdong-Hong Kong Joint Laboratory for Immune and Genetic Kidney Disease, 
      Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, 
      Guangzhou, and The Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, Li Ka Shing Institute of Health 
      Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese 
      University of Hong Kong, Hong Kong, China.
FAU - Yu, Xiyong
AU  - Yu X
AD  - Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key 
      Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth 
      Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, 
      China.
FAU - Lan, Hui-Yao
AU  - Lan HY
AD  - Guangdong-Hong Kong Joint Laboratory for Immune and Genetic Kidney Disease, 
      Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, 
      Guangzhou, and The Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, Li Ka Shing Institute of Health 
      Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese 
      University of Hong Kong, Hong Kong, China.
LA  - eng
PT  - Journal Article
DEP - 20200805
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC7475647
OTO - NOTNLM
OT  - Ang II
OT  - SIS3
OT  - TGF-beta/Smad
OT  - cardiac fibrosis and inflammation
OT  - hypertension
EDAT- 2020/09/22 06:00
MHDA- 2020/09/22 06:01
PMCR- 2020/08/05
CRDT- 2020/09/21 06:20
PHST- 2020/04/22 00:00 [received]
PHST- 2020/07/29 00:00 [accepted]
PHST- 2020/09/21 06:20 [entrez]
PHST- 2020/09/22 06:00 [pubmed]
PHST- 2020/09/22 06:01 [medline]
PHST- 2020/08/05 00:00 [pmc-release]
AID - S2329-0501(20)30169-8 [pii]
AID - 10.1016/j.omtm.2020.08.003 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2020 Aug 5;18:791-802. doi: 
      10.1016/j.omtm.2020.08.003. eCollection 2020 Sep 11.