GLP-1 signaling preserves cardiac function in endotoxemic Fischer 344 and DPP4-deficient rats.
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.
Ku
Hui-Chun
HC
Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei, 100, Taiwan.
Chen
Wen-Pin
WP
Su
Ming-Jai
MJ
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D019446:Endotoxemia / Q000503:physiopathology*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009102:Multiple Organ Failure / Q000517:prevention & control; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects*; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D008070:Lipopolysaccharides; D010455:Peptides; D014688:Venoms; D000099211:Phospholamban