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.

Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction

“…injection of cecal inoculum (200 mg/kg) as described previously (Brahmbhatt et al, 2005;Sharma et al, 1997;Gupta et al, 2004Gupta et al, , 2005a. Briefly, cecal inoculum was prepared by suspending 200 mg of freshly removed cecal material in 5 mL of sterile 5% dextrose water (D 5 W).…”

“…The estimation of the ET-1 concentration in the plasma and LV tissue supernatant was performed using an enzyme immuno assay (EIA) kit for ET-1 obtained from Assay Designs (Ann Arbor, MI) as described earlier (Brahmbhatt et al, 2005;Sharma et al, 1997;Gupta et al, 2004;Gupta et al, 2005a,b).…”

“…In vivo, we found that ET-1 precursor bigET-1 produced cardiac dysfunction in the septic rat heart (Brahmbhatt et al, 2005). Using isolated adult rat ventricular myocyte preparation, we demonstrated that bigET-1 produced a decompensatory contractile response via upregulation of p38-MAP phosphorylation, which correlated with an upregulated expression of cytosolic active caspase-3 (Gupta et al, 2004(Gupta et al, , 2005a. The regulation of molecular signaling and apoptosis in the myocardium during early (1-day, hyperdynamic state) and late (progressive hypodynamic state) sepsis are unknown.…”

Investigating the Effect of CoCl₂ Administration on Diabetic Nephropathy and Associated Aortic Dysfunction

“…The protein levels of endothelial nitric oxide synthase (eNOS) in thoracic aorta homogenate were determined using an ELISA kit (R&D Systems) according the manufacturer’s instructions and the tissue nitrate/nitrite (NOx) concentration was determined by using the Griess reaction [8] in Group 1, 2, 3 and 4.…”

Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes

“…Extracellular signal-regulated kinases (ERKs) are a subset of MAPKs that are activated in the heart during oxidative stress and sepsis [6,7]. In sepsis, the phosphorylation of ERK fosters the expression of TNF-α in several cell types including cardiomyocytes [8,9].…”