Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

Amy K.L. Banes-Berceli, Pimonrat Ketsawatsomkron, Safia Ogbi, Bela Patel, David M. Pollock, Mario B. Marrero

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT1 receptor antagonist, 10 mg·kg -1·day-1 orally in drinking water), atrasentan (ETA receptor antagonist, 10 mg·kg -1·day-1 orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg·kg-1·day-1 intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 ± 9.0, 130 ± 3.3, 128 ± 6.8, and 131 ± 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 ± 3.0, 92.6 ± 7.4, 76.9 ± 12.1, and 38.3 ± 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZinduced diabetes.

Original languageEnglish (US)
Pages (from-to)H1291-H1299
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number2
DOIs
StatePublished - Aug 1 2007

Keywords

  • Angiotensin II
  • Janus-activated kinase 2
  • Signal transducer and activator of transcription
  • Type 1 diabetes
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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