Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress

Alessandra Modesti, Iacopo Bertolozzi, Tania Gamberi, Matilde Marchetta, Camilla Lumachi, Mirella Coppo, Federico Moroni, Thomas Toscano, Gianluca Lucchese, Gian F. Gensini, Pietro A. Modesti

Research output: Contribution to journalArticle

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 μmol/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.

Original languageEnglish
Pages (from-to)394-401
Number of pages8
JournalDiabetes
Volume54
Issue number2
DOIs
Publication statusPublished - Feb 2005

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Modesti, A., Bertolozzi, I., Gamberi, T., Marchetta, M., Lumachi, C., Coppo, M., Moroni, F., Toscano, T., Lucchese, G., Gensini, G. F., & Modesti, P. A. (2005). Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress. Diabetes, 54(2), 394-401. https://doi.org/10.2337/diabetes.54.2.394