title: Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia.
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-alpha) 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, 208 Sudro Hall, Fargo, ND 58105, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.forename: Sachin
authors.initials: S
authors.lastname: Brahmbhatt
authors.forename: Avadhesh C
authors.initials: AC
authors.lastname: Sharma
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D019332:Endothelin-1 / Q000097:blood; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D011498:Protein Precursors / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018487:Ventricular Dysfunction, Left; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019332:Endothelin-1; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases