HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Modesti, A. Articles by Modesti, P. A. Search for Related Content PubMed PubMed Citation Articles by Modesti, A. Articles by Modesti, P. A. Social Bookmarking                What's this?

Hyperglycemia Activates JAK2 Signaling Pathway in Human Failing Myocytes via Angiotensin II–Mediated Oxidative Stress

¹ Department of Scienze Biochimiche, University of Florence, Florence, Italy
² Clinica Medica e Cardiologia, University of Florence, Florence, Italy
³ Institute of Thoracic and Cardiovascular Surgery, University of Siena, Siena, Italy

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.

Abbreviations: AGTN, angiotensinogen; Ang, angiotensin; AT1, Ang II type I; AT2, Ang II type II; DMEM, Dulbecco’s minimal essential medium; DPI, diphenyleneiodonium; ERk, extracellular signal–related kinase; JAK, Janus-activated kinase; MAPK, mitogen-activated protein kinase; RAS, renin-angiotensin system; ROS, reactive oxygen species

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Luptak, J. Yan, L. Cui, M. Jain, R. Liao, and R. Tian Long-Term Effects of Increased Glucose Entry on Mouse Hearts During Normal Aging and Ischemic Stress Circulation, August 21, 2007; 116(8): 901 - 909. [Abstract] [Full Text] [PDF]