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PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats

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Abstract

Objective

Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure.

Methods

We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis.

Results

We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI.

Conclusion

Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Mertes PM, Kindo M, Amour J, et al. Guidelines on enhanced recovery after cardiac surgery under cardiopulmonary bypass or off-pump. Anaesth Crit Care Pain Med. 2022;41(3):101059.

    Article  PubMed  Google Scholar 

  2. Rapp-Kesek D, Stridsberg M, Andersson LG, et al. Insulin resistance after cardiopulmonary bypass in the elderly patient. Scand Cardiovasc J. 2007;41(2):102–8.

    Article  CAS  PubMed  Google Scholar 

  3. Liang GY, Cai QY, Niu YM, et al. Cardiac glucose uptake and suppressed expression/translocation of myocardium glucose transport-4 in dogs undergoing ischemia-reperfusion. Exp Biol Med (Maywood). 2008;233(9):1142–8.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang DS, Liang GY, Liu DX, et al. Role of phosphorylated AMP-activated protein kinase (AMPK) in myocardial insulin resistance after myocardial ischemia-reperfusion during cardiopulmonary bypass surgery in dogs. Med Sci Monit. 2019;25:4149–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu B, Liang G, Xu G, et al. Intervention of rosiglitazone on myocardium Glut-4 mRNA expression during ischemia-reperfusion injury in cardio-pulmonary bypass in dogs. Mol Cell Biochem. 2013;373(1-2):279–84.

    Article  CAS  PubMed  Google Scholar 

  6. Yue TL, Bao W, Gu JL, et al. Rosiglitazone treatment in Zucker diabetic fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes. 2005;54(2):554–62.

    Article  CAS  PubMed  Google Scholar 

  7. Jaldin-Fincati JR, Pavarotti M, Frendo-Cumbo S, et al. Update on glut4 vesicle traffic: A cornerstone of insulin action. Trends Endocrinol Metab. 2017;28(8):597–611.

    Article  CAS  PubMed  Google Scholar 

  8. Liu Z, Yu M, Fei B, et al. Mir-21-5p targets PDHA1 to regulate glycolysis and cancer progression in gastric cancer. Oncol Rep. 2018;40(5):2955–63.

    CAS  PubMed  Google Scholar 

  9. Wang H, Lu J, Kulkarni S, et al. Metabolic and oncogenic adaptations to pyruvate dehydrogenase inactivation in fibroblasts. J Biol Chem. 2019;294(14):5466–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Whitley MJ, Arjunan P, Nemeria NS, et al. Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αv138m variant of human pyruvate dehydrogenase. J Biol Chem. 2018;293(34):13204–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu S, Liu CX, Xu W, et al. Butyrate induces apoptosis by activating pdc and inhibiting complex i through sirt3 inactivation. Signal Transduct Target Ther. 2017;2:16035.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pavlu-Pereira H, Lousa D, Tomé CS, et al. Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency. Biochimie. 2021;183:78–88.

    Article  CAS  PubMed  Google Scholar 

  13. Bedoyan JK, Hecht L, Zhang S, et al. A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (pdp1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep. 2019;48(1):26–35.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lissens W, De Meirleir L, Seneca S, et al. Mutations in the x-linked pyruvate dehydrogenase (e1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 2000;15(3):209–19.

    Article  CAS  PubMed  Google Scholar 

  15. Schummer CM, Werner U, Tennagels N, et al. Dysregulated pyruvate dehydrogenase complex in zucker diabetic fatty rats. Am J Physiol Endocrinol Metab. 2008;294(1):E88–96.

    Article  CAS  PubMed  Google Scholar 

  16. Lundsgaard AM, Sjøberg KA, Høeg LD, et al. Opposite regulation of insulin sensitivity by dietary lipid versus carbohydrate excess. Diabetes. 2017;66(10):2583–95.

    Article  CAS  PubMed  Google Scholar 

  17. Schöder H, Knight RJ, Kofoed KF, et al. Regulation of pyruvate dehydrogenase activity and glucose metabolism in post-ischaemic myocardium. Biochim Biophys Acta. 1998;1406(1):62–72.

    Article  PubMed  Google Scholar 

  18. Li J, Yang YL, Li LZ, et al. Succinate accumulation impairs cardiac pyruvate dehydrogenase activity through grp91-dependent and independent signaling pathways: Therapeutic effects of ginsenoside rb1. Biochim Biophys Acta Mol Basis Dis. 2017;1863(11):2835–47.

    Article  CAS  PubMed  Google Scholar 

  19. Zhao X, Zhang F, Wang Y. Proteomic analysis reveals Xuesaitong injection attenuates myocardial ischemia/reperfusion injury by elevating pyruvate dehydrogenase-mediated aerobic metabolism. Mol Biosyst. 2017;13(8):1504–11.

    Article  CAS  PubMed  Google Scholar 

  20. Li M, Xu S, Geng Y, et al. The protective effects of L-carnitine on myocardial ischaemia-reperfusion injury in patients with rheumatic valvular heart disease undergoing CPB surgery are associated with the suppression of NF-κB pathway and the activation of Nrf2 pathway. Clin Exp Pharmacol Physiol. 2019;46(11):1001–12.

    Article  CAS  PubMed  Google Scholar 

  21. Pan SS, Wang F, Hui YP, et al. Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury. Perfusion. 2022;4:2676591221099807.

    Google Scholar 

  22. Nakamura M, Sadoshima J. Cardiomyopathy in obesity, insulin resistance and diabetes. J Physiol. 2020;598(14):2977–93.

    Article  CAS  PubMed  Google Scholar 

  23. Floh AA, Manlhiot C, Redington AN, et al. Insulin resistance and inflammation are a cause of hyperglycemia after pediatric cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg. 2015;150(3):498–504.e1.

    Article  CAS  PubMed  Google Scholar 

  24. Wang Z, Wang Y, Han Y, et al. Akt is a critical node of acute myocardial insulin resistance and cardiac dysfunction after cardiopulmonary bypass. Life Sci. 2019;1(234):116734.

    Article  Google Scholar 

  25. Sun W, Quan N, Wang L, et al. Cardiac-specific deletion of the Pdha1 gene sensitizes heart to toxicological actions of ischemic stress. oxicol Sci. 2016;153(2):411.

    CAS  Google Scholar 

  26. Gopal K, Almutairi M, Al Batran R, et al. Cardiac-specific deletion of pyruvate dehydrogenase impairs glucose oxidation rates and induces diastolic dysfunction. Front Cardiovasc Med. 2018;5:17.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Opie LH. Myocardial metabolism and heart disease. Jpn Circ J. 1978;42(11):1223–47.

    Article  CAS  PubMed  Google Scholar 

  28. Sun J, Li J, Guo Z, et al. Overexpression of pyruvate dehydrogenase e1α subunit inhibits warburg effect and induces cell apoptosis through mitochondria-mediated pathway in hepatocellular carcinoma. Oncol Res. 2019;27(4):407–14.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bersin RM, Stacpoole PW. Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am Heart J. 1997 Nov;134(5 Pt 1):841–55.

    Article  CAS  PubMed  Google Scholar 

  30. Jin L, Cho M, Kim BS, et al. Drug evaluation based on phosphomimetic PDHA1 reveals the complexity of activity-related cell death in A549 non-small cell lung cancer cells. BMB Rep. 2021;54(11):563–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by grant from the National Natural Science foundation of China (No.82170286; No.81960051 and No.82160060); Project of High–Level Innovative Talents of Guizhou Province, No. [2016]4034; and Construction Funding from Characteristic Key Laboratory of Guizhou Province, No. [2021]313.

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Authors and Affiliations

  1. Department of Cardiovascular Surgery, the Affiliated Hospital of Guizhou Medical University, Beijing Road, Yunyan District, Guiyang, 550001, Guizhou Province, China

    Kai-Yuan Chen, Ying-Nan Song, Hong-Jin Chen, Si-Yuan Yang, Xuan-Yi Hu & Gui-You Liang

  2. Translational Medicine Research Center, Guizhou Medical University, Guiyang, 550025, Guizhou Province, China

    Kai-Yuan Chen, Zhou Liu, Yong-Peng Hui, Ying-Nan Song, Jun-Hou Lu, Hong-Jin Chen & Gui-You Liang

  3. Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou Province, China

    Jing Yi

  4. Department of Cardiovascular Surgery, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563009, Guizhou Province, China

    Deng-Shen Zhang

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  1. Kai-Yuan Chen
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Contributions

CKY and LGY: designed this study; SYN, LJH, and CHJ: conceptualization, methodology; LZ and YJ: software, statistical. CKY and HYP: data curation, experimental studies, drafted the manuscript. ZDS and YJ: manuscript preparation; LGY, YSY, and HXY: reviewing and editing, validation. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Gui-You Liang.

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Ethics Approval

The animal care and experimental procedures were authorized by the administrative departments and approved by the Animal Ethics Committee of Guizhou Medical University (Approval No.: 2000405), following the National Institutes of Health's Handbook for the Care and Use of Laboratory Animals.

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All authors certify that they have participated sufficiently in the work to take public responsibility for the appropriateness of the study design and method, and the collection, analysis, and interpretation of the data.

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The authors have reviewed the final version of the manuscript and approved it for publication. To the best of our knowledge and belief, this manuscript has not been published in whole or in part nor is it being considered for publication elsewhere.

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Chen, KY., Liu, Z., Yi, J. et al. PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07501-9

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