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

Ting-Lin Yen1,2, Po-Ching Chou3, Chia-Ti Tsai4

  • 1Department of Medical Research, Cathay General Hospital, 280 Renai Rd. Sec.4, Taipei City, 10630, Taiwan.

Cardiovascular Drugs and Therapy
|March 3, 2026
PubMed
Abstract

Insights

Dapagliflozin inhibits thrombin-induced ADAM17 activation, reducing vascular smooth muscle cell migration and neointimal hyperplasia. This SGLT2-independent mechanism offers a new therapeutic strategy for vascular restenosis and cardiovascular disease.

Area of Science:

  • Cardiovascular Biology
  • Pharmacology
  • Cell Signaling

Background:

  • Vascular restenosis after angioplasty is driven by vascular smooth muscle cell (VSMC) proliferation, migration, and fibrosis.
  • Thrombin promotes neointimal hyperplasia, a key factor in vascular restenosis.
  • Dapagliflozin (SGLT2 inhibitor) shows cardiovascular benefits independent of glucose lowering, but its effect on thrombin-mediated fibrosis is unknown.

Purpose of the Study:

  • To investigate the role of dapagliflozin in inhibiting thrombin-induced signaling pathways in VSMCs.
  • To determine if dapagliflozin affects ADAM17 activation and downstream signaling.
  • To evaluate the in vivo efficacy of dapagliflozin in a rat model of vascular injury.

Main Methods:

  • Assessed thrombin-stimulated ADAM17, ERK1/2, c-Jun, and CTGF in cultured A10 VSMCs using immunoblotting and migration assays.
  • Utilized cell-free kits for enzymatic activity assays of ADAM17 and thrombin.
  • Employed pharmacological inhibitors (TAPI-1 for ADAM17, U0126 for ERK) to define pathway hierarchy.
  • Investigated dapagliflozin's effect on neointimal formation in a rat carotid artery balloon injury model.

Main Results:

  • Thrombin increased ADAM17 phosphorylation, ERK1/2 and c-Jun activation, and CTGF expression in VSMCs.
  • Dapagliflozin suppressed these thrombin-induced responses concentration-dependently without affecting thrombin activity.
  • ADAM17 inhibition mimicked dapagliflozin's effects, identifying ADAM17 as a critical upstream mediator.
  • Dapagliflozin reduced VSMC migration in vitro and neointimal hyperplasia in vivo.

Conclusions:

  • Dapagliflozin inhibits thrombin-induced ADAM17 activation and downstream signaling (ERK/c-Jun/CTGF), thereby reducing VSMC migration and neointimal formation.
  • This SGLT2-independent mechanism highlights dapagliflozin's vasculoprotective potential.
  • ADAM17 presents a potential therapeutic target for preventing vascular restenosis and fibrosis-related cardiovascular diseases.
Keywords:
ADAM17CTGFDapagliflozinNeointimal hyperplasiaThrombin

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