Effect of obesity on insulin signaling through JAK2 in rat aorta

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyperactivated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyperactivated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyperactivated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases. (c) 2005 Elsevier Inc. All rights reserved.