Background. The results of several studies indicate that strict glycemic control and ANG II antagonism reduces cardiovascular morbidity and mortality in diabetic patients. Studies in vascular smooth muscle cells showed that both high glucose concentration and angiotensin II (ANG II), may enhance the generation of intracellular reactive oxygen species (ROS), able to stimulate growth-promoting kinases such as Janus-activated kinase (JAK2) which induces cytokine and fibrogenetic growth factors overexpression, but no information are available regarding human cardiomyocytes. Purpose and Methods. Aim of our study was to investigate whether hyperglycemia activates Ang-II generation and JAK2 signalling pathway in human myocytes. 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. Results. HG enhanced JAK2 phosphorylation vs normal glucose (5.5 mM) only in failing myocytes (+107%, p<0.05) with no detectable effect in non failing 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. Conclusions. In conclusion, hyperglycemia-induced JAK2 phosphorylation in human failing myocytes is mediated by increased ANG II generation and NADPH oxidase activation.
|Titolo:||Hyperglycemia activates ANG II autocrine production and following reactive oxygen species dependent JAK2 phosphorylation in isolated human failing myocytes|
|Anno di registrazione:||2004|
|Autori di Ateneo:|
|Autori:||PA Modesti; T Gamberi; C.Lumachi; M.Marchetta; S.Vanni; T Toscano; A Modesti; GF Gensini|
|Appare nelle tipologie:||1c - Abstract su rivista|