Activation of calpain-2 by mediators in pulmonary vascular remodeling of pulmonary arterial hypertension

Laszlo Kovacs, Weihong Han, Ruslan Rafikov, Zsolt Bagi, Stefan Offermanns, Takaomi C. Saido, Stephen Matthew Black, Yunchao Su

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Calpain mediates collagen synthesis and cell proliferation and plays an important role in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). In the present study, we investigated whether and how calpain is activated by PAH mediators in pulmonary artery smooth muscle cells (PASMCs). These data show that smooth muscle-specific knockout of calpain attenuated and knockout of calpastatin potentiated pulmonary vascular remodeling and pulmonary hypertension. Treatment of PASMCs with the PAH mediators platelet-derived growth factor (PDGF), serotonin, H 2 O 2 , endothelin-1, and IL-6 caused significant increases in calpain activity, cell proliferation, and collagen-I protein level without changes in protein levels of calpain-1 and -2. The calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA/AM) did not affect calpain activation, but the extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 and knocking down of calpain-2 prevented calpain activation in PAH mediator-treated PASMCs. Mass spectrometry data showed that the phosphorylation of calpain-2 at serine (Ser) 50 was increased and the phosphorylation of calpain-2 at Ser369 was decreased in PDGF-treated PASMCs. The PDGF-induced increase in Ser50 phosphorylation of calpain-2 was prevented by PD98059, whereas dephosphorylation of calpain-2 at Ser369 was blocked by the protein phosphatase 2A inhibitor fostriecin. Furthermore, smooth muscle of pulmonary arteries in PAH animal models and patients with PAH showed higher levels of phospho-Ser50-calpain-2 (P-Ser50) and lower levels of phospho-Ser369-calpain-2 (P-Ser369). These data support that calpain modulates pulmonary vascular remodeling in PAH. PAH mediator-induced activation of calpain is caused by ERK1/2-dependent phosphorylation of calpain-2 at Ser50 and protein phosphatase 2A-dependent dephosphorylation of calpain-2 at Ser369 in pulmonary vascular remodeling of PAH.

Original languageEnglish (US)
Pages (from-to)384-393
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2016

Fingerprint

Calpain
Pulmonary Hypertension
Chemical activation
Lung
Muscle
Phosphorylation
Pulmonary Artery
Smooth Muscle Myocytes
Platelet-Derived Growth Factor
Cells
Vascular Remodeling
Protein Phosphatase 2
Cell proliferation
Smooth Muscle
Collagen
Cell Proliferation
Ethane
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1

Keywords

  • H O
  • Platelet-derived growth factor
  • Pulmonary hypertension
  • Serotonin
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Activation of calpain-2 by mediators in pulmonary vascular remodeling of pulmonary arterial hypertension. / Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan; Bagi, Zsolt; Offermanns, Stefan; Saido, Takaomi C.; Black, Stephen Matthew; Su, Yunchao.

In: American journal of respiratory cell and molecular biology, Vol. 54, No. 3, 01.03.2016, p. 384-393.

Research output: Contribution to journalArticle

Kovacs, Laszlo ; Han, Weihong ; Rafikov, Ruslan ; Bagi, Zsolt ; Offermanns, Stefan ; Saido, Takaomi C. ; Black, Stephen Matthew ; Su, Yunchao. / Activation of calpain-2 by mediators in pulmonary vascular remodeling of pulmonary arterial hypertension. In: American journal of respiratory cell and molecular biology. 2016 ; Vol. 54, No. 3. pp. 384-393.
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