PMID- 38017499
OWN - NLM
STAT- MEDLINE
DCOM- 20231130
LR  - 20240313
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 22
IP  - 1
DP  - 2023 Nov 28
TI  - SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the 
      acetylation of endothelium Notch1.
PG  - 331
LID - 10.1186/s12933-023-02040-x [doi]
LID - 331
AB  - BACKGROUND: Endothelial-mesenchymal transition (EndMT) plays a crucial role in 
      promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin 
      (DAPA) is a sodium-glucose-linked transporter 2 (SGLT-2) inhibitor that has been 
      shown to improve cardiac function in non-diabetic patients with heart failure 
      (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects 
      are yet to be fully elucidated. METHODS: Isoproterenol (ISO) was used to generate 
      a HF model in mice. For in vitro experiments, we used TGF-beta1-stimulated human 
      umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells 
      (MAECs). RESULTS: Both our in vivo and in vitro results showed that EndMT 
      occurred with decreased SIRT1 (NAD(+)-dependent deacetylase) protein expression, 
      which could be reversed by DAPA therapy. We found that the protective effect of 
      DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we 
      observed that SIRT1 phosphorylation, a required modification for its 
      ubiquitination and degradation, was reduced by DAPA treatment, which induces the 
      nucleus translocation of SIRT1 and promotes its binding to the active 
      intracellular domain of Notch1 (NICD). This interaction led to the deacetylation 
      and degradation of NICD, and the subsequent inactivation of the Notch1 signaling 
      pathway which contributes to ameliorating EndMT. CONCLUSIONS: Our study revealed 
      that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This 
      beneficial effect is achieved through SIRT1-mediated deacetylation and 
      degradation of NICD. Our findings provide greater insight into the underlying 
      mechanisms of the therapeutic effects of DAPA in non-diabetic HF.
CI  - (c) 2023. The Author(s).
FAU - Wang, Weijie
AU  - Wang W
AD  - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical 
      University, 246 Xuefu Road, Harbin, 150086, China.
AD  - Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical 
      University, Harbin, China.
FAU - Li, Yilan
AU  - Li Y
AD  - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical 
      University, 246 Xuefu Road, Harbin, 150086, China.
AD  - Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical 
      University, Harbin, China.
FAU - Zhang, Yanxiu
AU  - Zhang Y
AD  - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical 
      University, 246 Xuefu Road, Harbin, 150086, China.
AD  - Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical 
      University, Harbin, China.
FAU - Ye, Tao
AU  - Ye T
AD  - Department of Organic Chemistry, College of Pharmacy, Harbin Medical University, 
      Harbin, China.
FAU - Wang, Kui
AU  - Wang K
AD  - Department of Organic Chemistry, College of Pharmacy, Harbin Medical University, 
      Harbin, China.
FAU - Li, Shuijie
AU  - Li S
AD  - Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical 
      University, Harbin, 150081, China. shuijie.li@hrbmu.edu.cn.
AD  - State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, 
      China. shuijie.li@hrbmu.edu.cn.
FAU - Zhang, Yao
AU  - Zhang Y
AD  - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical 
      University, 246 Xuefu Road, Harbin, 150086, China. yaozhang_grace@163.com.
AD  - Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical 
      University, Harbin, China. yaozhang_grace@163.com.
LA  - eng
GR  - 81770255/the National Natural Science Foundation of China/
GR  - KF202103/the Open Project of the Key Laboratory of Myocardial Ischemia/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231128
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - EC 3.5.1.- (SIRT1 protein, human)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Sirtuin 1/metabolism
MH  - Acetylation
MH  - Endothelium
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - *Epithelial-Mesenchymal Transition
PMC - PMC10685714
OTO - NOTNLM
OT  - Deacetylation
OT  - Endothelial-mesenchymal transition
OT  - Heart failure
OT  - SGLT-2 inhibitors
OT  - SIRT1
COIS- The authors have declared that no competing interest exists.
EDAT- 2023/11/29 06:42
MHDA- 2023/11/30 06:43
PMCR- 2023/11/28
CRDT- 2023/11/29 00:10
PHST- 2023/07/05 00:00 [received]
PHST- 2023/10/20 00:00 [accepted]
PHST- 2023/11/30 06:43 [medline]
PHST- 2023/11/29 06:42 [pubmed]
PHST- 2023/11/29 00:10 [entrez]
PHST- 2023/11/28 00:00 [pmc-release]
AID - 10.1186/s12933-023-02040-x [pii]
AID - 2040 [pii]
AID - 10.1186/s12933-023-02040-x [doi]
PST - epublish
SO  - Cardiovasc Diabetol. 2023 Nov 28;22(1):331. doi: 10.1186/s12933-023-02040-x.