DPP4 Deficiency Exerts Protective Effect against H2O2 Induced Oxidative Stress in Isolated Cardiomyocytes

Abstract

Apart from the antihyperglycemic effects, DPP4 inhibitors and GLP-1 molecules are involved in the preservation of cardiac functions. We have demonstrated that DPP4-deficient rats possess resistance to endotoxemia and ischemia/reperfusion stress. However, whether the decrease of DPP4 activity simply augmented the GLP-1 signaling or that such decrease resulted in a change of cellular function remain unclear. Accordingly, we investigated the responses of H2O2-induced oxidative stress in adult wild-type and DPP4-deficient rats isolated cardiomyocytes. The coadministration of GLP-1 or DPP4 inhibitor was also performed to define the mechanisms. Cell viability, ROS concentration, catalase activity, glucose uptake, prosurvival, proapoptotic signaling, and contractile function were examined after cells exposed to H2O2. DPP4-deficient cardiomyocytes were found to be resistant to H2O2-induced cell death via activating AKT signaling, enhancing glucose uptake, preserving catalase activity, diminishing ROS level and proapoptotic signaling. GLP-1 concentration-dependently improved cell viability in wild-type cardiomyocyte against ROS stress, and the ceiling response concentration (200 nM) was chosen for studies. GLP-1 was shown to decrease H2O2-induced cell death by its receptor-dependent AKT pathway in wild-type cardiomyocytes, but failed to cause further activation of AKT in DPP4-deficient cardiomyocytes. Acute treatment of DPP4 inhibitor only augmented the protective effect of low dose GLP-1, but failed to alter fuel utilization or ameliorate cell viability in wild-type cardiomyocytes after H2O2 exposure. The improvement of cell viability after H2O2 exposure was correlated with the alleviation of cellular contractile dysfunction in both DPP4-deficient and GLP-1 treated wild-type cardiomyocytes. These findings demonstrated that GLP-1 receptor-dependent pathway is important and exert protective effect in wild-type cardiomyocyte. Long term loss of DPP4 activity increased the capability against ROS stress, which was more than GLP-1 dependent pathway.

Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide

“…In addition, we found that silence of DPP4 inhibited superoxide generation induced by HNF1b knockdown in AML-12 hepatocytes, indicating that DPP4 also involved in HNF1b knockdown-associated superoxide generation. Previous studies have reported that DPP4 inhibitors played an antioxidant role mainly through regulating expression of antioxidant enzymes and mitochondrial ROS generation [42,43]. These results indicated that generation of superoxide induced by DPP4 also contributed to the ER tress, hepatic lipid accumulation and insulin resistance.…”

Effect of hyperoxic and hyperbaric conditions on the adenosinergic pathway and CD26 expression in rat

“…Third, CD26 controls energetic metabolism and energy supply to cells via degradation of peptides such as the glucagon-like peptide 1 (41). Last, but not least, a long-term loss of CD26 activity was reported to increase the capability against the oxidative stress and reactive oxygen species (38). Although addressing CD26 substrates was out of the scope of this work, monitoring them during hyperoxia certainly deserves further study.…”

Epac is Required for GLP-1R-Mediated Inhibition of Oxidative Stress and Apoptosis in Cardiomyocytes

“…The antiapoptotic effect of GLP-1 is PKA dependent because the improvement of cell viability of GLP-1 after H 2 O 2 exposure was blocked by H89, a PKA inhibitor (40). GLP-1 had an antiapoptotic activity mediated by a cAMP/PKA-dependent signaling pathway in ␤-cells (36) and endothelial cells (14).…”