Hypoxic Induction of Cox-2 Regulates Proliferation of Human Pulmonary Artery Smooth Muscle Cells

2002 ◽  
Vol 27 (6) ◽  
pp. 688-696 ◽  
Author(s):  
Xudong Yang ◽  
Karen K. K. Sheares ◽  
N. Davie ◽  
Paul D. Upton ◽  
Graham W. Taylor ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Hypoxic Induction ◽  
Pulmonary Artery Smooth Muscle ◽  
Cox 2 ◽  
Human Pulmonary Artery

scholarly journals Hypoxia-inducible factor-1α regulates KCNMB1 expression in human pulmonary artery smooth muscle cells

2012 ◽  
Vol 302 (3) ◽  
pp. L352-L359 ◽  
Author(s):  
Yong-Tae Ahn ◽  
Yu-Mee Kim ◽  
Eloa Adams ◽  
Shu-Chen Lyu ◽  
Cristina M. Alvira ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Acute Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Muscle Cells ◽  
Site Directed Mutagenesis ◽  
Hypoxic Induction ◽  
Pulmonary Artery Smooth Muscle ◽  
Human Pulmonary Artery

Previously, we observed that hypoxia increases the expression of the β1-subunit ( KCNMB1) of the calcium-sensitive potassium channel (BKCa). Herein, we elucidate the mechanism whereby hypoxia increases KCNMB1 expression in human pulmonary artery smooth muscle cells (hPASMC). In response to hypoxia, the expression of both the transcription factor hypoxia-inducible factor 1-α ( HIF-1α) and KCNMB1 are increased. Knockdown of HIF-1α using a shRNA plasmid blocked the hypoxic induction of KCNMB1 expression. Chromatin immunoprecipitation (ChIP) demonstrated HIF-1α binding to three discrete regions of the human KCNMB1 promoter known to contain hypoxia response elements (HREs). A KCNMB1 promoter reporter assay combined with site-directed mutagenesis identified two adjacent HREs located between −3,540 bp and −3,311 bp that are essential for the hypoxic induction of KCNMB1 promoter activity. Furthermore, additional ChIP assays demonstrated recruitment of the HIF-1α transcriptional coactivator, p300, to this same promoter region. Treatment of hPASMC with the histone deacetylase inhibitor, trichostatin, prolonged the increase in KCNMB1 observed with hypoxia, suggesting that alterations in chromatin remodeling function to limit the hypoxic induction of KCNMB1. Finally, KCNMB1 knockdown potentiated the hypoxia-induced increase in cytosolic calcium in hPASMC, highlighting the contribution of the β1-subunit in modulating vascular SMC tone in response to acute hypoxia. In conclusion, HIF-1α increases KCNMB1 expression in response to hypoxia in hPASMC by binding to two HREs located at −3,540 to −3,311 of the KCNMB1 promoter. We speculate that selective modulation of KCNMB1 expression may serve as a novel therapeutic approach to address diseases characterized by an increase in vascular tone.

Differential effects of TGF-β1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells

2004 ◽  
Vol 287 (5) ◽  
pp. L919-L927 ◽  
Author(s):  
Karen K. K. Sheares ◽  
Trina K. Jeffery ◽  
Lu Long ◽  
Xudong Yang ◽  
Nicholas W. Morrell
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Critical Role ◽  
Muscle Cells ◽  
Cyclooxygenase 2 ◽  
Hypoxic Induction ◽  
Pulmonary Artery Smooth Muscle ◽  
Cox 2 ◽  
Tgf Β1

Chronic hypoxia-induced pulmonary hypertension results partly from proliferation of smooth muscle cells in small peripheral pulmonary arteries. Previously, we demonstrated that hypoxia modulates the proliferation of human peripheral pulmonary artery smooth muscle cells (PASMCs) by induction of cyclooxygenase-2 (COX-2) and production of antiproliferative prostaglandins ( 55 ). The transforming growth factor (TGF)-β superfamily plays a critical role in the regulation of pulmonary vascular remodeling, although to date an interaction with hypoxia has not been examined. We therefore investigated the pathways involved in the hypoxic induction of COX-2 in peripheral PASMCs and the contribution of TGF-β1 and bone morphogenetic protein (BMP)-4 in this response. In the present study, we demonstrate that hypoxia induces activation of p38MAPK, ERK1/2, and Akt in PASMCs and that these pathways are involved in the hypoxic regulation of COX-2. Whereas inhibition of p38MAPK or ERK1/2 activity suppressed hypoxic induction of COX-2, inhibition of the phosphoinositide 3-kinase pathway enhanced hypoxic induction of COX-2. Furthermore, exogenous TGF-β1 induced COX-2 mRNA and protein expression, and our findings demonstrate that release of TGF-β1 by PASMCs during hypoxia contributes to the hypoxic induction of COX-2 via the p38MAPK pathway. In contrast, BMP-4 inhibited the hypoxic induction of COX-2 by an MAPK-independent pathway. Together, these findings suggest that the TGF-β superfamily is part of an autocrine/paracrine system involved in the regulation of COX-2 expression in the distal pulmonary circulation, and this modulates hypoxia-induced pulmonary vascular cell proliferation.

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