title: Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress.
abstract: Hyperglycemia was reported to enhance angiotensin (Ang) II generation in rat cardiomyocytes, and Ang II inhibition reduces cardiovascular morbidity and mortality in diabetic patients. In diabetic patients, the enhanced activation of intracellular pathways related with myocyte hypertrophy and gene expression might enhance the progression of cardiac damage. Therefore, we investigated the effects of glucose on Ang II-mediated activation of Janus-activated kinase (JAK)-2, a tyrosine kinase related with myocyte hypertrophy and cytokine and fibrogenetic growth factor overexpression, in ventricular myocytes isolated from nonfailing human hearts (n = 5) and failing human hearts (n = 8). In nonfailing myocytes, JAK2 phosphorylation was enhanced by Ang II only in the presence of high glucose (25 mmol/l) via Ang II type I (AT1) receptors (+79% vs. normal glucose, P < 0.05). JAK2 activation was prevented by inhibitors of reactive oxygen species (ROS) generation (diphenyleneiodonium [DPI], tiron, and apocynin). In myocytes isolated from failing hearts, JAK2 phosphorylation was enhanced by high glucose alone (+107%, P < 0.05). High glucose-induced JAK2 activation was blunted by both ACE inhibition (100 nmol/l ramipril) and AT1 antagonism (1 mumol/l valsartan), thus revealing that the effects are mediated by autocrine Ang II production. Inhibition of ROS generation also prevented high glucose-induced JAK2 phosphorylation. In conclusion, in human nonfailing myocytes, high glucose allows Ang II to activate JAK2 signaling, whereas in failing myocytes, hyperglycemia alone is able to induce Ang II generation, which in turn activates JAK2 via enhanced oxidative stress.
authors.affiliation: Department of Scienze Biochimiche, University of Florence, Florence, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Modesti
authors.forename: Iacopo
authors.initials: I
authors.lastname: Bertolozzi
authors.forename: Tania
authors.initials: T
authors.lastname: Gamberi
authors.forename: Matilde
authors.initials: M
authors.lastname: Marchetta
authors.forename: Camilla
authors.initials: C
authors.lastname: Lumachi
authors.forename: Mirella
authors.initials: M
authors.lastname: Coppo
authors.forename: Federico
authors.initials: F
authors.lastname: Moroni
authors.forename: Thomas
authors.initials: T
authors.lastname: Toscano
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lucchese
authors.forename: Gian F
authors.initials: GF
authors.lastname: Gensini
authors.forename: Pietro A
authors.initials: PA
authors.lastname: Modesti
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D053614:Janus Kinase 2; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014019:Tissue Donors
chemical_list: D011518:Proto-Oncogene Proteins; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2