Abstract:
:In addition to its role as a vasoconstrictor, angiotensin II also acts as a potent growth factor by activating several tyrosine kinases, including Jak2. Interestingly, Jak2 has been linked to similar cardiovascular pathologies as have been previously linked to the renin-angiotensin system. Identifying the downstream targets of Jak2 via the AT(1) receptor may therefore elucidate its role in the progression of various pathologies. Previously, microarray analysis from our laboratory identified the Type 1 inositol 1,4,5 trisphosphate (IP(3)) receptor as a potential target of Jak2 following chronic stimulation by angiotensin II. Therefore, we hypothesized that Jak2 regulates IP(3) receptor expression in response to angiotensin II. To test this hypothesis, rat aortic smooth muscle (RASM) cells over-expressing a dominant negative (DN) Jak2 protein were used. The Jak2-dependent signaling in these cells is reduced approximately 90% when compared to RASM control cells. Analysis of protein expression showed that the IP(3) receptor was degraded approximately 2-fold (P<0.05) in cells lacking functional Jak2 within 1 h of treatment by angiotensin II. Notably, degradation of the IP(3) receptor was reversible since protein levels were restored to normal following 2 h of recovery from angiotensin II. To eliminate the possibility of clonal artifact in the DN cells, wild type RASM cells were treated with the Jak2 pharmacological inhibitor, AG490. We found that angiotensin II treatment degraded IP(3) receptor in AG490-treated cells, but not in the vehicle controls. Treatment with lactacystin, a proteasome inhibitor, completely blocked angiotensin II-mediated degradation of IP(3) receptor, thereby suggesting that the degradation occurs through a proteasome-dependent mechanism. Moreover, the degradation of IP(3) receptor in DN cells correlated with a significant loss of intracellular calcium mobilization when treated with angiotensin II (DN 27.4+/-1.1% vs. WT 42.2+/-4.7%; n=5, P=0.002). We next examined through what mechanism Jak2 regulates the IP(3) receptor. When wild type RASM cells were treated with PP2, an Src-family inhibitor, IP(3) receptor expression was markedly reduced. Since previous data show that Fyn, a downstream target of Jak2, is able to phosphorylate the IP(3) receptor at Tyr 353, we believe our data suggest that Jak2 prevents the angiotensin II-mediated IP(3) receptor degradation through the activation of Fyn. In conclusion, these data suggest that Jak2 has a protective role in maintaining IP(3) receptor expression, potentially through activation of Fyn and subsequent phosphorylation of the IP(3) receptor.
journal_name
Vascul Pharmacoljournal_title
Vascular pharmacologyauthors
Wallace TA,Xia SL,Sayeski PPdoi
10.1016/j.vph.2005.08.022keywords:
subject
Has Abstractpub_date
2005-11-01 00:00:00pages
336-45issue
5eissn
1537-1891issn
1879-3649pii
S1537-1891(05)00187-4journal_volume
43pub_type
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journal_title:Vascular pharmacology
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doi:10.1016/j.vph.2008.02.002
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doi:10.1016/j.vph.2006.01.002
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journal_title:Vascular pharmacology
pub_type: 杂志文章
doi:10.1016/j.vph.2006.10.002
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journal_title:Vascular pharmacology
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journal_title:Vascular pharmacology
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doi:10.1016/j.vph.2006.09.001
更新日期:2007-02-01 00:00:00
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journal_title:Vascular pharmacology
pub_type: 杂志文章
doi:10.1016/j.vph.2004.11.003
更新日期:2005-03-01 00:00:00
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journal_title:Vascular pharmacology
pub_type: 杂志文章
doi:10.1016/j.vph.2005.01.003
更新日期:2005-01-01 00:00:00
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doi:10.1016/j.vph.2006.11.004
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