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Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia
Biochimica et Biophysica Acta - Molecular Basis of Disease
  • A. Gupta
  • S. Brahmbhatt
  • Avadhesh C. Sharma, Philadelphia College of Osteopathic Medicine
Document Type
Article
Publication Date
1-1-2004
Disciplines
Abstract
We hypothesized that sepsis during hyperglycemia would activate left ventricular (LV) mitogen activated protein kinase (MAPK) signaling mechanisms and modulate generation of endothelin-1 (ET-1) and nitric oxide (NO) that can contribute to the progression of LV dysfunction. A single injection of streptozotocin (STZ, 60 mg/kg, via tail vein) was used to produce type 2 diabetes in male SD rats. Polymicrobial sepsis and sham-sepsis were induced using single i.p. injection of cecal inoculum and sterile 5% dextrose water, respectively, on the 13th and 27th day following STZ injection. Both 2-week (2-wk) and 4-wk diabetes groups were associated with hyperglycemia and weight loss. LV end diastolic pressure (LVEDP) was significantly increased in 4-wk diabetes but not in 2-wk diabetes group. Plasma concentration of tumor necrosis factor-alpha (TNF-α) was significantly increased in 4-wk diabetes+sepsis group as compared to sham, 2-wk diabetes+sepsis and sepsis groups. Elevated plasma and LV ET-1 and NO byproducts (NOx) along with LV preproET-1 and inducible nitric oxide synthase (iNOS) protein expression were observed in 4-wk but not in 2-wk diabetes group. Sepsis further elevated LV iNOS and preproET-1 in 4-wk diabetes group. Up-regulated phosphorylation of LV p38-MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein-27 (Hsp27) was observed in 4-wk diabetes group. Sepsis caused a factorial increase in LV p38-MAPK and Hsp27 phosphorylation and iNOS up-regulation but not ERK1/2 following progression from 2-wk to 4-wk diabetes. The study provides evidence that sepsis up-regulated LV iNOS, p38-MAPK phosphorylation and elevated LVEDP during 4-wk diabetes. We concluded that sepsis contributes in the development of LVEDP dysfunction and alteration in signaling mechanisms depending upon the progression from 2-wk to 4-wk diabetes in the rat. © 2004 Elsevier B.V. All rights reserved.
Comments

This article was published in Biochimica et Biophysica Acta - Molecular Basis of Disease, Volume 1690, Issue 1, Pages 42-53.

The published version is available at http://dx.doi.org/10.1016/j.bbadis.2004.05.001.

Copyright © 2004.

Citation Information
A. Gupta, S. Brahmbhatt and Avadhesh C. Sharma. "Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia" Biochimica et Biophysica Acta - Molecular Basis of Disease Vol. 1690 Iss. 1 (2004) p. 42 - 53
Available at: http://works.bepress.com/avadhesh_sharma/44/