Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat

Abstract

Background: Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure-prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model.

Methods and results: At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1-treated SHHF rats had greater survival (72% versus 44%, P=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1-treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1-treated SHHF rats.

Conclusions: Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis.

Keywords: apoptosis; glucose; heart failure; mortality.

Figure 1

The survival of two groups of SHHF randomized to receive intraperitoneal continuous infusion of GLP-1 or saline. GLP treated animals had better survival compared to control (p =0.008).

Figure 2

Percent of myocyte and non myocyte cells staining positive for TUNEL at 9 months (n=5 in each group) and 12 months of in a group treated with GLP-1 (n=6) compared to saline control (n=5). There was significantly less myocyte apoptosis in the GLP-1 group at 12 months. There was no difference in non-myocyte apoptosis. *p = 0.0002 saline control at 9 versus 12 months. ** p = 0.03 GLP-1 compared to control at 12 months.

Figure 3

Western blots for caspase-3 protein (32 kDa) and activated, cleaved form of caspase-3 (21 kDa). GLP-1 treatment was associated with decreased caspase-3 activation.

Figure 4

The effects of GLP-1 on myocardial GLP-1 receptor expression (A), threonine phosphorylation of Akt (B), serine phosphorylation of Akt (C) and myocardial GLUT-4 translocation (D). GLP-1 receptor expression was upregulated in the GLP-1 treated group at 12 months (p = 0.043). There was increased Akt phosphorylation and activation in the GLP-1 treated group (p=0.025 for serine and p = 0.018 for threonine) with resultant increase in GLUT-4 translocation (p =0.043).