Hyperglycemia was reported to enhance myocyte Angiotensin (Ang)-II generation and Ang-II antagonism reduces cardiovascular morbidity and mortality in diabetic patients. Janus-activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which induces cytokine and fibrogenetic growth factors overexpression, was reported to be activated by Ang-II in neonatal myocytes but no information are available in adult myocytes. We hypothesised that hyperglycemia activates JAK2 signalling pathway in human failing myocytes via Ang-II generation. Therefore we investigated the effects of high glucose concentration (HG, 25 mM for 6 hours) on human myocytes (1x105 cell/ml) isolated from failing explanted hearts (n=4) and tentative donors (n=3) in the presence of Ang II antagonism. JAK2 phosphorylation was investigated by Western blot analysis. HG enhanced JAK2 phosphorylation vs normal glucose (5.5 mM) only in failing myocytes (+107%, p<0.05) with no detectable effect in NF cells. JAK2 activation was mediated by myocyte production of Ang II as shown by the inhibitory effects of co-incubation with ACE inhibitor (ramipril, 100 nM) or AT1 antagonist (valsartan, 1 µM). The inhibition of NADPH oxidase (DPI, 100 µM) prevented HG induced JAK2 phosphorylation. In conclusion, hyperglycemia induced Ang II generation in human failing myocytes which in turn induces JAK2 phosphorylation via enhanced oxidative stress related with NADPH oxidase activation.
|Titolo:||P3431 Hyperglycemia activates JAK2 signalling pathway in human falling myocytes via Ang II mediated oxidative stress|
|Anno di registrazione:||2003|
|Autori di Ateneo:|
|Autori:||Modesti PA; Vanni S; Gamberi T; Toscano T; Bertolozzi I; Modesti A|
|Appare nelle tipologie:||1c - Abstract su rivista|