GLP-1 signaling preserves cardiac function in endotoxemic Fischer 344 and DPP4-deficient rats

Abstract

Glucagon-like peptide-1 (GLP-1) is rapidly cleaved by widely expressed dipeptidyl peptidase-4 (DPP4) enzyme. Both DPP4 inhibitors and GLP-1 analogue are being developed as a novel class of oral antihyperglycemic agent in the treatment of diabetes. However, the benefits of both agents on the cardiovascular function of endotoxemic animals remains poorly understood. In this study, the cardiac function of wild-type and DPP4-deficient rats was evaluated by pressure-volume loops in control and 4 h after lipopolysaccharide (LPS, 10 mg/kg, i.v.) treatment. LPS-induced suppression of cardiovascular function in wild-type rats was associated with a significant reduction in cardiac cAMP level, phosphorylation of phospholamban, and attenuation of aortic contractile response to phenylephrine. DPP4-deficient rats had better preservation of cardiovascular function than wild-type rats during endotoxemia, which was correlated with a more prominent elevation of GLP-1 signaling. These findings coincided with the pretreatment of GLP-1 analogue, exendin-4, where the deterioration of cardiovascular function during endotoxemia was significantly reversed in wild-type rats. Furthermore, the benefit of DPP4 deficiency or GLP-1 analogue not only preserved cardiovascular function but also alleviated multiple organ injury and improved survival rate during endotoxemia. In summary, this study demonstrated that the resistance to LPS in DPP4-deficient rats seems to be derived from the higher GLP-1 production, and exendin-4 prevents cardiac dysfunction in wild-type rats with endotoxemia. This study proves that GLP-1 agonists or DPP4 inhibitor may possibly be used as a preventive or even as a novel therapeutic agent in septic shock.

Renal and Cardiac Effects of DPP-4 Inhibitors – from Preclinical Development to Clinical Research

“…Cardiovascular function was preserved in DPP-4 -/-rats (versus wild-type animals) during endotoxemia and septic shock and these findings coincided with observations in wild-type animals pre-treated with the GLP-1 analogue, exendin-4 [63]. An alternative pathway through which GLP-1 may exert its effects has recently been identified [64].…”

“…In diabetic ZDF rats, sitagliptin was associated with a significant normalization of blood pressure in ZDF rats with elevated blood pressure (versus non-diabetic ZDF rats) [44], whereas vildagliptin showed no influence on blood pressure in hypertensive OLEFT rats [45]. By contrast, DPP-4 -/-and exendin-4 attenuated the severe hypotension associated with endotoxemia and septic shock in wild-type rats [63]. These effects were considered most likely to be the result of the positive inotropic effects of GLP-1 (effected via the GLP-1 receptor).…”

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

“…Experimental evidence suggests beneficial effects of GLP-1 during sepsis, with reduced mortality being found in endotoxin-challenged DPP-4 knockout rats and activation of the GLP-1 receptor improving prognosis in the same model (39). Mechanistically this might be mediated by anti-inflammatory capacities of GLP-1, leading to reduced oxidative stress and tissue protection (40,41).…”

DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion

“…Cardiac function was estimated in vivo by a pressurevolume catheter (1.9 F; Scisense Instruments, Ontario, Canada) as described previously Ku et al 2010). The catheter was inserted into the carotid artery and then advanced into the left ventricle for the measurement of pressure and volume.…”