Related Experiment Video
Updated: Aug 22, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during
Akanksha Gupta1, Sachin Brahmbhatt, Avadhesh C Sharma
1Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, 208 Sudro Hall, Fargo, ND 58105, USA.
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.
Insights
Sepsis exacerbates left ventricular (LV) dysfunction in diabetic rats by activating mitogen-activated protein kinase (MAPK) signaling and increasing endothelin-1 (ET-1) and nitric oxide (NO) production, particularly in later stages of diabetes.
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Molecular Biology
Background:
- Sepsis and diabetes mellitus are significant global health concerns.
- Both conditions can independently lead to cardiovascular complications, including left ventricular (LV) dysfunction.
- The interplay between sepsis and diabetes in modulating cardiac signaling pathways remains incompletely understood.
Purpose of the Study:
- To investigate the effects of sepsis on LV mitogen-activated protein kinase (MAPK) signaling, endothelin-1 (ET-1), and nitric oxide (NO) generation in a rat model of type 2 diabetes.
- To determine how the duration of diabetes influences the cardiac response to sepsis.
Main Methods:
- Type 2 diabetes was induced in male Sprague-Dawley rats using streptozotocin (STZ).
- Polymicrobial sepsis or sham-sepsis was induced at 2-week and 4-week post-STZ injection.
- LV end-diastolic pressure (LVEDP), plasma cytokine levels (TNF-alpha), ET-1, nitric oxide byproducts (NOx), and protein expression of preproET-1, iNOS, and MAPK pathway components were assessed.
Main Results:
- Four-week diabetes with sepsis significantly increased LVEDP, plasma TNF-alpha, and LV ET-1 and NOx levels compared to controls.
- Sepsis further elevated LV inducible nitric oxide synthase (iNOS) and preproET-1 expression in 4-week diabetic rats.
- Increased phosphorylation of LV p38-MAPK and heat shock protein-27 (Hsp27) was observed in 4-week diabetic rats, with sepsis exacerbating this effect.
Conclusions:
- Sepsis up-regulates LV iNOS, p38-MAPK phosphorylation, and elevates LVEDP in 4-week diabetic rats.
- The progression of diabetes significantly influences the cardiac response to sepsis, affecting signaling mechanisms and LV function.
- These findings suggest that sepsis contributes to LV dysfunction in diabetes through altered signaling pathways dependent on disease duration.