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DPP4 deficiency exerts protective effect against H2O2 induced oxidative stress in isolated cardiomyocytes
Hui-Chun Ku1, Wen-Pin Chen, Ming-Jai Su
1Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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 H(2)O(2)-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 H(2)O(2). DPP4-deficient cardiomyocytes were found to be resistant to H(2)O(2)-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 H(2)O(2)-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 H(2)O(2) exposure. The improvement of cell viability after H(2)O(2) 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.
Insights
DPP4-deficient cardiomyocytes resist oxidative stress by activating AKT signaling and enhancing glucose uptake. This long-term DPP4 deficiency offers greater protection against reactive oxygen species than GLP-1 signaling alone.
Area of Science:
- Cardiovascular Biology
- Metabolic Diseases
- Cellular Physiology
Background:
- Dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) molecules influence cardiac function beyond glucose control.
- DPP4-deficient rats exhibit resistance to stress, but the mechanisms underlying this protection, whether solely through GLP-1 augmentation or altered cellular function, remain unclear.
Purpose of the Study:
- To investigate the protective mechanisms of DPP4 deficiency against hydrogen peroxide (H2O2)-induced oxidative stress in isolated cardiomyocytes.
- To elucidate the roles of GLP-1 signaling and DPP4 inhibition in modulating cardiomyocyte response to oxidative stress.
Main Methods:
- Isolated adult cardiomyocytes from wild-type and DPP4-deficient rats were exposed to H2O2, with or without GLP-1 or DPP4 inhibitor.
- Assessed cell viability, reactive oxygen species (ROS) levels, catalase activity, glucose uptake, prosurvival/proapoptotic signaling, and contractile function.
Main Results:
- DPP4-deficient cardiomyocytes showed resistance to H2O2-induced death, characterized by activated AKT signaling, enhanced glucose uptake, preserved catalase activity, reduced ROS, and suppressed proapoptotic pathways.
- GLP-1 improved wild-type cardiomyocyte viability via its receptor-dependent AKT pathway, but did not further activate AKT in DPP4-deficient cells.
- DPP4 inhibition alone had limited effects on wild-type cardiomyocyte viability or metabolism under oxidative stress.
- Improved cell viability correlated with alleviated contractile dysfunction in both DPP4-deficient and GLP-1 treated cardiomyocytes.
Conclusions:
- The GLP-1 receptor-dependent pathway confers protection to wild-type cardiomyocytes against oxidative stress.
- Long-term absence of DPP4 activity enhances cardiomyocyte resilience to reactive oxygen species, exceeding the protective capacity of the GLP-1 dependent pathway alone.
