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Potential Role of Dipeptidyl Peptidase−4 in Regulating Mitochondria and Oxidative Stress in Cardiomyocytes

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Abstract

Oxidative stress causes mitochondrial damage and bioenergetic dysfunction and inhibits adenosine triphosphate production, contributing to the pathogenesis of cardiac diseases. Dipeptidyl peptidase 4 (DPP4) is primarily a membrane-bound extracellular peptidase that cleaves Xaa-Pro or Xaa-Ala dipeptides from the N terminus of polypeptides. DPP4 inhibitors have been used in patients with diabetes and heart failure; however, they have led to inconsistent results. Although the enzymatic properties of DPP4 have been well studied, the substrate-independent functions of DPP4 have not. In the present study, we knocked down DPP4 in cultured cardiomyocytes to exclude the effects of differential alteration in the substrates and metabolites of DPP4 then compared the response between the knocked-down and wild-type cardiomyocytes during exposure to oxidative stress. H2O2 exposure induced DPP4 expression in both types of cardiomyocytes. However, knocking down DPP4 substantially reduced the loss of cell viability by preserving mitochondrial bioenergy, reducing intracellular reactive oxygen species production, and reducing apoptosis-associated protein expression. These findings demonstrate that inhibiting DPP4 improves the body’s defense against oxidative stress by enhancing Nrf2 and PGC-1α signaling and increasing superoxide dismutase and catalase activity. Our results indicate that DPP4 mediates the body’s response to oxidative stress in individuals with heart disease.

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Data Availability

No datasets were generated or analyzed during the current study.

Abbreviations

ATP:

Adenosine triphosphate

ARE:

Antioxidant responsive elements

DHE:

Dihydroethidium

DPP4:

Dipeptidyl peptidase-4

Drp1:

Dynamin-related protein 1

FCCP:

Cyanide-4-(trifluoromethoxy) phenylhydrazone

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GLP-1:

Glucagon-like peptide-1

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

Mfn1:

Mitofusin 1

Nrf2:

Nuclear factor erythroid 2–related factor 2

PARP:

Poly (ADP-ribose) polymerase

PGC-1ɑ:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

OCR:

Oxygen consumption rate

ROS:

Reactive oxygen species

SDS:

Sodium dodecyl sulfate

SOD:

Superoxide dismutases

TBST:

Tris-buffered saline with Tween 20

TMRM:

Tetramethylrhodamine

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Acknowledgements

We like to thank the research funding from Ministry of Science and Technology, Taiwan (MOST 106-2321-B-030-002-MY3) and (MOST 109-2320-B-030-006-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, MacKay Memorial Hospital, Taipei, Taiwan

    Shih-Yi Lee

  2. MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan

    Shih-Yi Lee

  3. Department of Life Science, Fu Jen Catholic University, No.510, Zhongzheng Rd., **nzhuang Dist., New Taipei City, 242, Taiwan

    Shao-Tung Wu, Chen-Xuan Du & Hui-Chun Ku

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  1. Shih-Yi Lee
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  2. Shao-Tung Wu
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Contributions

Conceived and designed the experiments: HCK. Performed the experiments: SYL, SDW, CHD, HCK. Analyzed the data: SYL, SDW, CHD, HCK. Wrote the manuscript: SYL, HCK. All authors reviewed the manuscript.

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Correspondence to Hui-Chun Ku.

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Lee, SY., Wu, ST., Du, CX. et al. Potential Role of Dipeptidyl Peptidase−4 in Regulating Mitochondria and Oxidative Stress in Cardiomyocytes. Cardiovasc Toxicol (2024). https://doi.org/10.1007/s12012-024-09884-z

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