BMP4 increases canonical transient receptor potential protein expression by activating p38 MAPK and ERK1/2 signaling pathways in pulmonary arterial smooth muscle cells

Xiaoyan Li, Wenju Lu, Xin Fu, Yi Zhang, Kai Yang, Nanshan Zhong, Pixin Ran, Jian Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Abnormal bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of pulmonary hypertension. We previously foundthat BMP4 elevatedbasal intracellular Ca2+ ([Ca2+]i) concentrations in distal pulmonary arterial smooth muscle cells (PASMCs), attributable in large part to enhanced store-operated Ca2+ entry through store-operated Ca2+ channels (SOCCs). Moreover, BMP4 up-regulated the expression of canonical transient receptorpotential (TRPC) proteins thought tocomposeSOCCs.Thepresent study investigated the signaling pathways through which BMP4 regulates TRPC expression and basal [Ca 2+]i in distal PASMCs. Real-time quantitative PCR was used for the measurement of mRNA, Western blotting was used for the measurement of protein, and fluorescent microscopic for [Ca2+]i was used to determine the involvement of p38 and extracellular regulated kinase (ERK)-1/2 mitogen-activated protein kinase (MAPK) signaling in BMP4-induced TRPC expression and the elevation of [Ca2+]i in PASMCs. We found that the treatment of BMP4 led to the activation of both p38MAPK and ERK1/2 in rat distal PASMCs. The induction of TRPC1, TRPC4, and TRPC6 expression, and the increases of [Ca2+]i caused by BMP4 in distal PASMCs, were inhibited by treatment with either SB203580 (10 μM), the selective inhibitor for p38 activation, or the specific p38 small interfering RNA (siRNA). Similarly, those responses induced by BMP4 were also abolished by treatment with PD98059 (5 μM), the selective inhibitor of ERK1/2, orby the knockdown of ERK1/2 using its specific siRNA. These results indicate that BMP4 participates in the regulation of Ca2+ signaling in PASMCs bymodulating TRPC channel expression via activating p38 and ERK1/2MAPK pathways.

Original languageEnglish (US)
Pages (from-to)212-220
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number2
DOIs
StatePublished - Aug 2013

Keywords

  • BMP4
  • ERK1/2
  • Intracellular Ca concentration
  • P38 MAPK
  • TRPC

ASJC Scopus subject areas

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

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