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1 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: abanes{at}mcg.edu.
Serotonin is a vasoconstrictor and mitogen whose levels are elevated in diabetes. Previous studies have shown the presence of 5-HT2A, 5-HT2B and 5-HT1B receptors in vascular smooth muscle cells (VSMC). There is currently no data on 5-HT2B and 5-HT1B activation of the JAK/STAT pathway in VSMC and resultant potential alterations in 5-HT signaling in diabetes. Therefore, we tested the hypothesis that 5-HT differentially activates the JAK/STAT pathway in VSMC under conditions of normal (5 mM) and high (25 mM)glucose. Treatment of rat VSMC with 5-HT (10-6 M) resulted in time-dependent activation (~2 fold) of JAK2, JAK1 and STAT1 but not STAT3 (maximal at 5 min; returned to baseline by 30 minutes). The 5-HT2B receptor agonist BW723C86 and the 5-HT1B receptor agonist CGS12066A (10-9 to 10-5 M, 5 min stimulation) did not activate the JAK/STAT pathway. Treatment with the 5-HT2A receptor antagonist ketanserin (10 nM) inhibited JAK2 activation by 5-HT. Treatment of STZ-induced diabetic rats with ketanserin (5 mg/kg/day) reduced activation of JAK2 and STAT1 but not STAT3 in endothelium-denuded thoracic aorta in vivo. 5-HT (10-6 M) treatment resulted in increased cell proliferation and increased DNA synthesis which were inhibited by the JAK2 inhibitor AG490. Further studies with apocynin, DPI, catalase and virally transfected superoxide dismutase (SOD) had no effect in either glucose concentration on activation of the JAK/STAT pathway by 5-HT. Therefore we conclude that 5-HT activates JAK2, JAK1 and STAT1 via the 5-HT2A receptors in a reactive oxygen species independent manner under both normal and high glucose conditions.
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