Assessment of cardiac inflammation and remodeling during the development of streptozotocin-induced diabetic cardiomyopathy in vivo: A time course analysis

Abstract

In this study, we examined cardiac inflammation, fibrosis and left ventricular (LV) function during the development of streptozotocin (STZ)-induced diabetic cardiomyopathy using an animal model of diabetes mellitus (DM). Diabetes was induced in 22 Sprague‑Dawley rats by an intraperitoneal single injection of STZ (70 mg/kg). Non-diabetic animals served as the controls (n=6). LV function was documented using the conductance catheter technique 2 and 6 weeks after the induction of diabetes. Cardiac tissue was analyzed for cardiac immune cell infiltration, oxidative stress and remodeling in rats with STZ-induced diabetes at 2 different time points by immunohistochemistry. Cardiac function was significantly impaired in the diabetic animals. After 2 weeks, the induction of diabetes resulted in impaired cardiac function indexed by a decrease in systolic and diastolic LV function. This impairment of LV performance continued for up to 6 weeks after the STZ injection. This was associated with an increase in cardiac CD3+ and CD8a+ immune cell invasion and fibrosis, indexed by an increase in collagen content (p<0.05). Furthermore, oxidative stress response and matrix remodeling were increased after 2 weeks and this continued for up to 6 weeks after the induction of diabetes. In conclusion, cardiac dysfunction is associated with cardiac inflammation and adverse remodeling in experimental diabetic cardiomyopathy. Our results suggest that the model of STZ-induced diabetic cardiomyopathy is a robust model for investigating cardiac immune response and LV remodeling processes under diabetic conditions.

The co-occurrence of myocardial dysfunction and peripheral insensate neuropathy in a streptozotocin-induced rat model of diabetes

“…Becher et al, using a Sprague-Dawley STZ-DM model (single STZ [70 mg/kg] injection) and using the conductance Millar catheter technique, found significant changes in left ventricular relaxation that occurred at 2 weeks post STZ injection. Impaired relaxation was exemplified by increases in left ventricular diastolic relaxation time (msec) and decreases in left ventricular diastolic relaxation (mm Hg/sec), these changes were also found in conjunction with decreases in cardiac output and decreased left ventricular contractility (mm Hg/sec), indicating reduced systolic function [33]. Changes in cardiac structure, such as cardiac dilation were evident at 4 weeks, exemplified by increased left ventricular end diastolic and systolic dimensions and decreases in relative wall thickness.…”

Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy

“…Using mouse or rat models of type I diabetes they also demonstrated that neutralization of TNFα [120] or genetic deletion of kinin receptor B [121] attenuated the development of experimental diabetic cardiomyopathy associated with a reduction of intramyocardial inflammation and cardiac fibrosis. They also showed that inhibition of p38 mitogen-activated protein kinase attenuated left ventricular dysfunction by decreasing the level of myocardial pro-inflammatory cardiac cytokines in a mouse model of diabetes mellitus[122], and more recently they suggested that the STZ-induced diabetic cardiomyopathy is a robust model for investigating cardiac immune response and LV remodeling processes under diabetic conditions [123]. Several studies from other groups have also found similar pro-inflammatory changes in the myocardium of diabetic rodent hearts [37, 38, 41].…”

Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol

“…Although different mechanisms have been proposed for the development of the diabetic cardiomyopathy (DCM) phenotype, most available data suggest that cellular oxidative stress and moderate inflammation constitute early cardiac responses to hyperglycemia and associated metabolic alterations [2,3,4]. …”