Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs

Jian Wang, Xin Fu, Kai Yang, Qian Jiang, Yuqin Chen, Jing Jia, Xin Duan, Elizabeth W. Wang, Jianxing He, Pixin Ran, Nanshan Zhong, Gregg L Semenza, Wenju Lu

Research output: Contribution to journalArticle

Abstract

Aims Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca2+ concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca2+]i increases in hypoxic PASMCs. Methods and results The level of BMP4 mature protein was increased for 183% in distal pulmonary arterial smooth muscle (PA) from CH (10% O2 for 21 days; CH) exposed rats, and 143% in PASMCs cultured under prolonged hypoxia (4% O2 for 60 h). In rat PASMCs, HIF-1α overexpression up-regulated, whereas HIF-1α knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca2+]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for 80%, which was absent in HIF-1α heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca2+]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1α knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1α or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca2+]i. Conclusions BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca2+]i in PASMCs, promoting CHPH pathogenesis.

Original languageEnglish (US)
Pages (from-to)108-118
Number of pages11
JournalCardiovascular Research
Volume107
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

Bone Morphogenetic Protein 4
Hypoxia-Inducible Factor 1
Smooth Muscle Myocytes
Up-Regulation
Lung
Pulmonary Hypertension
Hypoxia
Small Interfering RNA
Smooth Muscle

Keywords

  • Basal[Ca<sup>2+</sup>]<inf>i</inf>
  • BMP4
  • HIF-1
  • PASMCs
  • TRPC

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs. / Wang, Jian; Fu, Xin; Yang, Kai; Jiang, Qian; Chen, Yuqin; Jia, Jing; Duan, Xin; Wang, Elizabeth W.; He, Jianxing; Ran, Pixin; Zhong, Nanshan; Semenza, Gregg L; Lu, Wenju.

In: Cardiovascular Research, Vol. 107, No. 1, 01.07.2015, p. 108-118.

Research output: Contribution to journalArticle

Wang, J, Fu, X, Yang, K, Jiang, Q, Chen, Y, Jia, J, Duan, X, Wang, EW, He, J, Ran, P, Zhong, N, Semenza, GL & Lu, W 2015, 'Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs', Cardiovascular Research, vol. 107, no. 1, pp. 108-118. https://doi.org/10.1093/cvr/cvv122
Wang, Jian ; Fu, Xin ; Yang, Kai ; Jiang, Qian ; Chen, Yuqin ; Jia, Jing ; Duan, Xin ; Wang, Elizabeth W. ; He, Jianxing ; Ran, Pixin ; Zhong, Nanshan ; Semenza, Gregg L ; Lu, Wenju. / Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs. In: Cardiovascular Research. 2015 ; Vol. 107, No. 1. pp. 108-118.
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abstract = "Aims Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca2+ concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca2+]i increases in hypoxic PASMCs. Methods and results The level of BMP4 mature protein was increased for 183{\%} in distal pulmonary arterial smooth muscle (PA) from CH (10{\%} O2 for 21 days; CH) exposed rats, and 143{\%} in PASMCs cultured under prolonged hypoxia (4{\%} O2 for 60 h). In rat PASMCs, HIF-1α overexpression up-regulated, whereas HIF-1α knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca2+]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for 80{\%}, which was absent in HIF-1α heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca2+]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1α knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1α or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca2+]i. Conclusions BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca2+]i in PASMCs, promoting CHPH pathogenesis.",
keywords = "Basal[Ca<sup>2+</sup>]<inf>i</inf>, BMP4, HIF-1, PASMCs, TRPC",
author = "Jian Wang and Xin Fu and Kai Yang and Qian Jiang and Yuqin Chen and Jing Jia and Xin Duan and Wang, {Elizabeth W.} and Jianxing He and Pixin Ran and Nanshan Zhong and Semenza, {Gregg L} and Wenju Lu",
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T1 - Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs

AU - Wang, Jian

AU - Fu, Xin

AU - Yang, Kai

AU - Jiang, Qian

AU - Chen, Yuqin

AU - Jia, Jing

AU - Duan, Xin

AU - Wang, Elizabeth W.

AU - He, Jianxing

AU - Ran, Pixin

AU - Zhong, Nanshan

AU - Semenza, Gregg L

AU - Lu, Wenju

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Aims Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca2+ concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca2+]i increases in hypoxic PASMCs. Methods and results The level of BMP4 mature protein was increased for 183% in distal pulmonary arterial smooth muscle (PA) from CH (10% O2 for 21 days; CH) exposed rats, and 143% in PASMCs cultured under prolonged hypoxia (4% O2 for 60 h). In rat PASMCs, HIF-1α overexpression up-regulated, whereas HIF-1α knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca2+]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for 80%, which was absent in HIF-1α heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca2+]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1α knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1α or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca2+]i. Conclusions BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca2+]i in PASMCs, promoting CHPH pathogenesis.

AB - Aims Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca2+ concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca2+]i increases in hypoxic PASMCs. Methods and results The level of BMP4 mature protein was increased for 183% in distal pulmonary arterial smooth muscle (PA) from CH (10% O2 for 21 days; CH) exposed rats, and 143% in PASMCs cultured under prolonged hypoxia (4% O2 for 60 h). In rat PASMCs, HIF-1α overexpression up-regulated, whereas HIF-1α knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca2+]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for 80%, which was absent in HIF-1α heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca2+]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1α knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1α or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca2+]i. Conclusions BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca2+]i in PASMCs, promoting CHPH pathogenesis.

KW - Basal[Ca<sup>2+</sup>]<inf>i</inf>

KW - BMP4

KW - HIF-1

KW - PASMCs

KW - TRPC

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