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
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Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Massachusetts Gen Hosp, Gen Med Serv, Boston, MA 02114 USA
Harvard Med Sch, Cambridge, MA USAMassachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Du, Lili
[1
,2
,5
]
Roberts, Jesse D., Jr.
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机构:
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Massachusetts Gen Hosp, Gen Med Serv, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA
Harvard Med Sch, Cambridge, MA USAMassachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
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
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.
机构:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Casteel, Darren E.
Zhang, Tong
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Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Zhang, Tong
Zhuang, Shunhui
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Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Zhuang, Shunhui
Pilz, Renate B.
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Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
机构:
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Harvard Univ, Sch Med, Cambridge, MA 02138 USAMassachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Chen, Jingsi
Roberts, Jesse D., Jr.
论文数: 0引用数: 0
h-index: 0
机构:
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Harvard Univ, Sch Med, Cambridge, MA 02138 USA
Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USAMassachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
机构:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Casteel, Darren E.
Zhang, Tong
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h-index: 0
机构:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Zhang, Tong
Zhuang, Shunhui
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h-index: 0
机构:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Zhuang, Shunhui
Pilz, Renate B.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA
机构:
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Harvard Univ, Sch Med, Cambridge, MA 02138 USAMassachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Chen, Jingsi
Roberts, Jesse D., Jr.
论文数: 0引用数: 0
h-index: 0
机构:
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Harvard Univ, Sch Med, Cambridge, MA 02138 USA
Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USAMassachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA