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
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