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Chymase induces profibrotic response via transforming growth factor-beta 1/Smad activation in rat cardiac fibroblasts

Xiao-Yan Zhao1, Lian-You Zhao, Qiang-Sun Zheng

  • 1Department of Cardiology, Key Laboratory of Hypertension, Tangdu Hospital, Fourth Military Medical University, No 1, Xinsi Street, Baqiao District, Xi'an, Shaanxi 710038, PR China.

Molecular and Cellular Biochemistry
|December 7, 2007
PubMed

Insights

Mast cell-derived chymase promotes cardiac fibroblast proliferation and collagen synthesis, key factors in myocardial fibrosis. This occurs through the transforming growth factor-beta 1 (TGF-beta1)/Smad signaling pathway, not angiotensin II.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Fibrosis Research

Background:

  • Mast cell-derived chymase is linked to myocardial fibrosis (MF).
  • The intracellular signaling mechanisms driving chymase-induced MF are not fully understood.
  • Transforming growth factor-beta 1 (TGF-beta1) and Smad proteins are crucial in fibrosis, with potential cross-talk with mitogen-activated protein kinase (MAPK) pathways.

Purpose of the Study:

  • To investigate if chymase activates the TGF-beta1/Smad pathway.
  • To determine the role of this pathway in chymase-induced cardiac fibroblast (CFs) proliferation and collagen synthesis.
  • To explore the involvement of angiotensin II and MAPK signaling in this process.

Main Methods:

  • Neonatal rat cardiac fibroblasts were used.
  • Cell proliferation was assessed using MTT assay.
  • Collagen synthesis was measured by 3H-Proline incorporation.
  • Gene and protein expression (TGF-beta1, p-Smad2/3) were analyzed via RT-PCR and Western blot.
  • Functional assays involved TGF-beta1 neutralizing antibody and angiotensin II receptor blockade.

Main Results:

  • Chymase dose-dependently increased CFs proliferation and collagen synthesis.
  • Chymase upregulated TGF-beta1 expression and phosphorylated-Smad2/3 protein levels.
  • Blocking TGF-beta1 inhibited chymase-induced effects, while blocking angiotensin II receptors did not.
  • Inhibition of MAPK signaling did not affect Smad activation by chymase.

Conclusions:

  • Chymase promotes cardiac fibroblast proliferation and collagen synthesis.
  • The TGF-beta1/Smad pathway mediates chymase's profibrotic effects.
  • Angiotensin II and MAPK signaling are not the primary mediators in this chymase-induced profibrotic action.
  • These findings elucidate a key mechanism in chymase-related myocardial fibrosis.

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