Circulation Research. 2001
Published online before print October 25, 2001, doi: 10.1161/hh2301.100806
Published online before print October 25, 2001, doi: 10.1161/hh2301.100806
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Submitted on December 4, 2000
Revised on October 16, 2001
Accepted on October 16, 2001
Shear Stress Regulates Endothelial Nitric Oxide Synthase Expression Through c-Src by Divergent Signaling Pathways
From the Division of Cardiology (M.E.D., H.C., G.R.D., D.G.H.) and the Molecular and Systems Pharmacology Program (M.E.D., D.G.H.), Emory University, Atlanta, Ga; and the Atlanta Veterans Hospital Medical Center (M.E.D., H.C., G.R.D., D.G.H.), Atlanta, Ga.
* To whom correspondence should be addressed. E-mail: dharr02{at}emory.edu.
In this study, we defined the signaling cascade responsible for increased eNOS mRNA expression in response to laminar shear stress. This pathway depends on the tyrosine kinase c-Src because shear induction of eNOS mRNA is blocked by the c-Src inhibitors PP1 and PP2, as well as an adenovirus encoding kinase inactive c-Src. After activation of c-Src, this pathway diverges. One arm is responsible for the short-term (6 hour) increase in eNOS mRNA. This involves a transient, 1-hour increase in eNOS transcription, as detected by nuclear run-on, that is dependent on activation of Ras and is blocked by adenoviral infection with dominant negative Ras. Downstream of Ras, MEK1/2 and ERK1/2 are important in this pathway, as 2 inhibitors of MEK1/2, PD98059 and UO126, completely prevented this early increase in eNOS mRNA. ERK1/2 was rapidly phosphorylated in response to shear, and this was prevented by c-Src and Ras inhibition. Further, Raf is phosphorylated in response to shear stress, and this is prevented by c-Src inhibition, suggesting that Raf may transduce the signal between Ras and ERK1/2. The second arm of the pathway linking activation of c-Src to eNOS expression involves stabilization of eNOS mRNA by shear stress. This response to shear is completely abrogated by the c-Src inhibitor PP1 but not altered by Ras or MEK1/2 inhibition. Thus, c-Src plays a central role in modulation of eNOS expression in response to shear stress via divergent pathways involving a short-term increase in eNOS transcription and a longer-term stabilization of eNOS mRNA.
Key words: shear stress • eNOS • c-Src • ERK1/2 • Raf • mRNA stability
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