Transforming growth factor-β downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling

被引:10
作者
Du, Lili [1 ,2 ,5 ]
Roberts, Jesse D., Jr. [1 ,2 ,3 ,4 ,5 ]
机构
[1] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Gen Med Serv, Boston, MA 02114 USA
[3] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA
[4] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA
[5] Harvard Med Sch, Cambridge, MA USA
关键词
pulmonary vascular smooth muscle cells; soluble guanylate cyclase; transforming growth factor-beta signaling; SOLUBLE GUANYLATE-CYCLASE; DEPENDENT PROTEIN-KINASE; RIGHT-VENTRICULAR HYPERTROPHY; NITRIC-OXIDE; TGF-BETA; GENE-EXPRESSION; NUCLEAR TRANSLOCATION; BIPHASIC ACTIVATION; MOLECULAR-CLONING; DEVELOPING LUNG;
D O I
10.1152/ajplung.00319.2018
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
TGF beta activation during newborn lung injury decreases the expression of pulmonary artery smooth muscle cell (PASMC)-soluble guanylate cyclase (sGC), a critical mediator of nitric oxide signaling. Using a rat PASMC line (CS54 cells), we determined how TGF beta downregulates sGC expression. We found that TGF beta decreases sGC expression through stimulating its type I receptor; TGF beta type I receptor (TGF beta R1) inhibitors prevented TGF beta-1-mediated decrease in sGC beta 1 subunit mRNA levels in the cells. However, TGF beta R1-Smad mechanisms do not regulate sGC; effective knockdown of Smad2 and Smad3 expression and function did not protect sGC alpha 1 mRNA levels during TGF beta-1 exposure. A targeted small-molecule kinase inhibitor screen suggested that MEK signaling regulates sGC expression in TGF beta-stimulated PASMC. TGF beta activates PASMC MEK/ERK signaling; CS54 cell treatment with TGF beta-1 increased MEK and ERK phosphorylation in a biphasic, time- and dose-dependent manner. Moreover, MEK/ERK activity appears to be required for TGF beta-mediated sGC expression inhibition in PASMC; MEK and ERK inhibitors protected sGC beta 1 mRNA expression in TGF beta-1-treated CS54 cells. Nuclear ERK activity is sufficient for sGC regulation; heterologous expression of a nucleusretained, constitutively active ERK2-MEK1 fusion protein decreased CS54 cell sGC alpha 1 mRNA levels. The in vivo relevance of this TGF beta-MEK/ERK-sGC downregulation pathway is suggested by the detection of ERK activation and sGC alpha 1 protein expression downregulation in TGF beta-associated mouse pup hyperoxic lung injury, and the determination that ERK decreases sGC alpha 1 protein expression in TGF beta-1-treated primary PASMC obtained from mouse pups. These studies identify MEK/ERK signaling as an important pathway by which TGF beta regulates sGC expression in PASMC.
引用
收藏
页码:L20 / L34
页数:15
相关论文
共 105 条
  • [1] Fyn and JAK2 mediate Ras activation by reactive oxygen species
    Abe, J
    Berk, BC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (30) : 21003 - 21010
  • [2] ROLE OF ENDOTHELIUM-DERIVED RELAXING FACTOR DURING TRANSITION OF PULMONARY CIRCULATION AT BIRTH
    ABMAN, SH
    CHATFIELD, BA
    HALL, SL
    MCMURTRY, IF
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1990, 259 (06): : H1921 - H1927
  • [3] Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia
    Alejandre-Alcazar, Miguel A.
    Kwapiszewska, Grazyna
    Reiss, Irwin
    Amarie, Oana V.
    Marsh, Leigh M.
    Sevilla-Perez, Julia
    Wygrecka, Malgorzata
    Eul, Bastian
    Koebrich, Silke
    Hesse, Mareike
    Schermuly, Ralph T.
    Seeger, Werner
    Eickelberg, Oliver
    Morty, Rory E.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2007, 292 (02) : L537 - L549
  • [4] Transforming growth factor-β signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung
    Ambalavanan, Namasivayam
    Nicola, Teodora
    Hagood, James
    Bulger, Arlene
    Serra, Rosa
    Murphy-Ullrich, Joanne
    Oparil, Suzanne
    Chen, Yiu-Fai
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2008, 295 (01) : L86 - L95
  • [5] Soluble guanylate cyclase modulates alveolarization in the newborn lung
    Bachiller, Patricia R.
    Cornog, Katherine H.
    Kato, Rina
    Buys, Emmanuel S.
    Roberts, Jesse D., Jr.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2013, 305 (08) : L569 - L581
  • [6] Transforming growth factor-β modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells
    Bachiller, Patricia R.
    Nakanishi, Hidehiko
    Roberts, Jesse D., Jr.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2010, 298 (03) : L324 - L334
  • [7] Benjamini Y, 2001, ANN STAT, V29, P1165
  • [8] sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension
    Black, SM
    Sanchez, LS
    Mata-Greenwood, E
    Bekker, JM
    Steinhorn, RH
    Fineman, JR
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2001, 281 (05) : L1051 - L1057
  • [9] Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs
    Black, SM
    Johengen, MJ
    Soifer, SJ
    [J]. PEDIATRIC RESEARCH, 1998, 44 (06) : 821 - 830
  • [10] Pulmonary vascular dysfunction in preterm lambs with chronic lung disease
    Bland, RD
    Ling, CY
    Albertine, KH
    Carlton, DP
    MacRitchie, AJ
    Day, RW
    Dahl, MJ
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2003, 285 (01) : L76 - L85