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Dapagliflozin Inhibits Thrombin Induced ADAM17 Phosphorylation and Downstream ERK/p-c-Jun-mediated CTGF Induction to Prevent Neointimal Hyperplasia.

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Τίτλος: Dapagliflozin Inhibits Thrombin Induced ADAM17 Phosphorylation and Downstream ERK/p-c-Jun-mediated CTGF Induction to Prevent Neointimal Hyperplasia.
Συγγραφείς: Yen TL; Department of Medical Research, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan.; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, 250, Wu Hsing St., Taipei, 110, Taiwan., Chou PC; Division of Interventional Cardiology, Department of Cardiovascular Center, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan., Tsai CT; Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung Shan S. Rd., Taipei City, 100225, C.T.T, Taiwan., Chen YL; Department of Medical Research, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan.; Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan., Chen CY; Division of General Cardiology, Department of Cardiovascular Center, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan., Chien YF; Department of Internal Medicine, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan., Ko WC; Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan. wckcgh@ms17.hinet.net.; School of Medicine, College of Medicine, Fu Jen Catholic University, 510, Zhongzheng Rd., Xinzhuang Dist, New Taipei City, 242062, Taiwan. wckcgh@ms17.hinet.net.
Πηγή: Cardiovascular drugs and therapy [Cardiovasc Drugs Ther] 2026 Aug; Vol. 40 (4), pp. 1403-1417. Date of Electronic Publication: 2026 Mar 03.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Kluwer Academic For The International Society For Cardiovascular Pharmacotherapy Country of Publication: United States NLM ID: 8712220 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-7241 (Electronic) Linking ISSN: 09203206 NLM ISO Abbreviation: Cardiovasc Drugs Ther Subsets: MEDLINE
Imprint Name(s): Publication: Norwell Ma : Kluwer Academic For The International Society For Cardiovascular Pharmacotherapy
Original Publication: [Norwell, MA] : Martinus Nijhoff Pub., [c1987-
Ιατρικοί όροι (MeSH): ADAM17 Protein*/metabolism , ADAM17 Protein*/antagonists & inhibitors , Benzhydryl Compounds*/pharmacology , Neointima*/prevention & control , Connective Tissue Growth Factor*/metabolism , Thrombin*/pharmacology , Glucosides*/pharmacology, Phosphorylation/drug effects ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/pathology ; Muscle, Smooth, Vascular/enzymology ; Cell Movement/drug effects ; Carotid Artery Injuries/pathology ; Carotid Artery Injuries/drug therapy ; Carotid Artery Injuries/enzymology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/pathology ; Myocytes, Smooth Muscle/enzymology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Animals ; Hyperplasia ; Rats ; Rats, Sprague-Dawley ; Male ; Signal Transduction ; Cell Line
Περίληψη: Purpose: Vascular restenosis following angioplasty remains a major clinical challenge driven by excessive vascular smooth muscle cell (VSMC) migration, proliferation, and fibrosis. Thrombin, a potent signaling molecule beyond its coagulative function, promotes neointimal hyperplasia. Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to exert cardiovascular protection independent of its glucose-lowering effects, yet its role in thrombin-mediated fibrotic signaling remains unclear.
Methods: Cultured A10 vascular smooth muscle cells were used to evaluate thrombin- stimulated A Disintegrin And Metalloprotease 17 (ADAM17), ERK1/2, c-Jun, and connective tissue growth factor (CTGF) by immunoblotting and migration analyses. Enzymatic activity (ADAM17 and thrombin) assays were tested by cell-free system kit. Pharmacological inhibition of ADAM17 by TAPI-1 and extracellular signal-regulated kinase (ERK) by U0126 were employed to delineate pathway hierarchy. An in vivo rat carotid artery balloon injury model was used to assess the effects of dapagliflozin on neointimal formation.
Results: Thrombin stimulation markedly increased ADAM17 phosphorylation, ERK1/2 and c-Jun activation, and CTGF expression in A10 cells. Dapagliflozin significantly suppressed these responses in a concentration-dependent manner without affecting thrombin enzymatic activity. Inhibition of ADAM17 recapitulated the effects of dapagliflozin, confirming ADAM17 as a key upstream mediator of thrombin-induced ERK/c-Jun/CTGF signaling. Functionally, dapagliflozin attenuated VSMC migration in vitro and significantly reduced neointimal hyperplasia in the rat carotid artery balloon injury model.
Conclusion: Dapagliflozin inhibits thrombin-induced ADAM17 activation and downstream ERK1/2-c-Jun-CTGF signaling, thereby limiting VSMC migration and neointimal formation after vascular injury. This SGLT2-independent mechanism provides new insight into the pleiotropic vasculoprotective actions of dapagliflozin and identifies ADAM17 as a potential therapeutic target for preventing vascular restenosis and fibrosis-related cardiovascular disease.
(© 2026. The Author(s).)
Competing Interests: Declarations. Ethics approval: Ethical approval was obtained from the Institutional Animal Care and Use Committee of Cathay General Hospital (approval number: CGH-IACUC-113-019). This study adheres to internationally accepted standards for animal research, following the 3Rs principle. The ARRIVE guidelines and the Guide for the Care and Use of Laboratory Animals (8th edition, National Research Council) were employed for reporting experiments involving live animals, promoting ethical research practices. Patient consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
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Grant Information: CGH-MR-A11426 Cathay General Hospital
Contributed Indexing: Keywords: ADAM17; CTGF; Dapagliflozin; Neointimal hyperplasia; Thrombin
Substance Nomenclature: EC 3.4.24.86 (ADAM17 Protein)
0 (Benzhydryl Compounds)
139568-91-5 (Connective Tissue Growth Factor)
EC 3.4.21.5 (Thrombin)
1ULL0QJ8UC (dapagliflozin)
0 (Glucosides)
EC 3.4.24.86 (Adam17 protein, rat)
EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
0 (Proto-Oncogene Proteins c-jun)
Entry Date(s): Date Created: 20260303 Date Completed: 20260721 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13388336
DOI: 10.1007/s10557-026-07857-8
PMID: 41774351
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1573-7241
DOI:10.1007/s10557-026-07857-8