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

Autor: Amy K.L. Banes-Berceli, Bela Patel, Mario B. Marrero, Pimonrat Ketsawatsomkron, Safia Ogbi, David M. Pollock
Rok vydání: 2007
Předmět:
Blood Glucose
Male
Pyrrolidines
Time Factors
Physiology
Tetrazoles
Aorta
Thoracic
Blood Pressure
Protein Tyrosine Phosphatase
Non-Receptor Type 11
Phosphorylation
Protein Tyrosine Phosphatase
Non-Receptor Type 1
Endothelin-1
Angiotensin II
Protein Tyrosine Phosphatase
Non-Receptor Type 6
Intracellular Signaling Peptides and Proteins
JAK-STAT signaling pathway
Tyrphostins
Receptor
Endothelin A
Endothelin A Receptor Antagonists
Vasodilation
STAT1 Transcription Factor
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.drug
STAT3 Transcription Factor
medicine.medical_specialty
Biology
Receptor
Angiotensin
Type 1
Diabetes Mellitus
Experimental
Physiology (medical)
Internal medicine
Diabetes mellitus
Renin–angiotensin system
medicine
Animals
Protein Kinase Inhibitors
Biphenyl Compounds
Atrasentan
Janus Kinase 2
medicine.disease
Endothelin 1
Rats
Enzyme Activation
Endocrinology
STAT protein
Benzimidazoles
Protein Tyrosine Phosphatases
Angiotensin II Type 1 Receptor Blockers
Diabetic Angiopathies
Zdroj: American Journal of Physiology-Heart and Circulatory Physiology. 293:H1291-H1299
ISSN: 1522-1539
0363-6135
DOI: 10.1152/ajpheart.00181.2007
Popis: 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 STZ-induced diabetes.
Databáze: OpenAIRE
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