BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs

Yi Zhang, Yingfeng Wang, Kai Yang, Lichun Tian, Xin Fu, Yan Wang, Yueqian Sun, Qian Jiang, Wenju Lu, Jian Wang

Research output: Contribution to journalArticle

Abstract

Multiple abnormalities of bone morphogenetic protein (BMPs) signaling are implicated in the process of pulmonary arterial hypertension (PAH). BMP4 plays an important role during the process of pulmonary arterial remodeling and mutant of the principle BMP4 receptor, BMP receptors II (BMPRII), is found to associate with the development of PAH. However, the likely mechanism defining the contribution of BMPRII to BMP4 mediated signaling in pulmonary arterial smooth muscle cells (PASMCs) remains comprehensively unclear. We previously found that enhanced store operated calcium entry (SOCE) and basal intracellular calcium concentration [Ca2+]i were induced by BMP4 via upregulation of TRPC1, 4 and 6 expression in PASMCs, and that BMP4 modulated TRPC channel expression through activating p38MAPK and ERK1/2 signaling pathways. In this study, BMPRII siRNA was used to knockdown BMPRII expression to investigate whether BMP4 upregulates the expression of TRPC and activating Smad1/5/8, ERK1/2 and p38MAPK pathway via BMPRII in distal PASMCs. Our results showed that knockdown of BMPRII: 1) attenuated BMP4 induced activation of P-Smad1/5/8, without altering BMP4 induced P-p38MAPK and P-ERK1/2 activation in PASMCs; 2) did not attenuate the BMP4-induced TRPC1, 4 and 6 expression; 3) did not affect BMP4-enhanced SOCE and basal [Ca2+]i. Thus, we concluded that BMP4 activated Smad1/5/8 pathway is BMPRII-dependent, while the BMP4 - ERK/p-P38 - TRPC - SOCE signaling axis are likely mediated through other receptor rather than BMPRII.

Original languageEnglish (US)
Article numbere112695
JournalPLoS One
Volume9
Issue number12
DOIs
StatePublished - Dec 2 2014

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Bone Morphogenetic Protein Receptors
MAP Kinase Signaling System
smooth muscle
myocytes
Smooth Muscle Myocytes
Muscle
lungs
calcium
Lung
receptors
Calcium
Pulmonary Hypertension
bone morphogenetic proteins
Type II Bone Morphogenetic Protein Receptors
Up-Regulation
Chemical activation
Multiple Abnormalities
hypertension
Bone Morphogenetic Proteins
Calcium Signaling

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs. / Zhang, Yi; Wang, Yingfeng; Yang, Kai; Tian, Lichun; Fu, Xin; Wang, Yan; Sun, Yueqian; Jiang, Qian; Lu, Wenju; Wang, Jian.

In: PLoS One, Vol. 9, No. 12, e112695, 02.12.2014.

Research output: Contribution to journalArticle

Zhang, Y, Wang, Y, Yang, K, Tian, L, Fu, X, Wang, Y, Sun, Y, Jiang, Q, Lu, W & Wang, J 2014, 'BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs', PLoS One, vol. 9, no. 12, e112695. https://doi.org/10.1371/journal.pone.0112695
Zhang, Yi ; Wang, Yingfeng ; Yang, Kai ; Tian, Lichun ; Fu, Xin ; Wang, Yan ; Sun, Yueqian ; Jiang, Qian ; Lu, Wenju ; Wang, Jian. / BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs. In: PLoS One. 2014 ; Vol. 9, No. 12.
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AU - Zhang, Yi

AU - Wang, Yingfeng

AU - Yang, Kai

AU - Tian, Lichun

AU - Fu, Xin

AU - Wang, Yan

AU - Sun, Yueqian

AU - Jiang, Qian

AU - Lu, Wenju

AU - Wang, Jian

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AB - Multiple abnormalities of bone morphogenetic protein (BMPs) signaling are implicated in the process of pulmonary arterial hypertension (PAH). BMP4 plays an important role during the process of pulmonary arterial remodeling and mutant of the principle BMP4 receptor, BMP receptors II (BMPRII), is found to associate with the development of PAH. However, the likely mechanism defining the contribution of BMPRII to BMP4 mediated signaling in pulmonary arterial smooth muscle cells (PASMCs) remains comprehensively unclear. We previously found that enhanced store operated calcium entry (SOCE) and basal intracellular calcium concentration [Ca2+]i were induced by BMP4 via upregulation of TRPC1, 4 and 6 expression in PASMCs, and that BMP4 modulated TRPC channel expression through activating p38MAPK and ERK1/2 signaling pathways. In this study, BMPRII siRNA was used to knockdown BMPRII expression to investigate whether BMP4 upregulates the expression of TRPC and activating Smad1/5/8, ERK1/2 and p38MAPK pathway via BMPRII in distal PASMCs. Our results showed that knockdown of BMPRII: 1) attenuated BMP4 induced activation of P-Smad1/5/8, without altering BMP4 induced P-p38MAPK and P-ERK1/2 activation in PASMCs; 2) did not attenuate the BMP4-induced TRPC1, 4 and 6 expression; 3) did not affect BMP4-enhanced SOCE and basal [Ca2+]i. Thus, we concluded that BMP4 activated Smad1/5/8 pathway is BMPRII-dependent, while the BMP4 - ERK/p-P38 - TRPC - SOCE signaling axis are likely mediated through other receptor rather than BMPRII.

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