Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function

Acta Pharmacologica Sinica volume 44, pages 2184–2200 (2023)Cite this article

Abstract

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara△CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The expression of PPARα and its target genes are decreased in LPS-treated heart tissue.
Fig. 2: Myeloid cell-specific Ppara deficiency has no significant effect in LPS-induced cardiac dysfunction.
Fig. 3: Cardiomyocyte-specific Ppara knockout potentiates LPS-induced cardiac dysfunction and cardiac inflammation.
Fig. 4: LPS-induced mitochondrial dysfunction is exacerbated in cardiac tissue of PparaΔCM mice.
Fig. 5: Cardiomyocytes-specific Ppara disruption potentiates LPS-induced fatty acid metabolism dysfunction.
Fig. 6: Cardiomyocytes-specific Ppara disruption potentiates LPS-induced mitophagy.
Fig. 7: Cardiomyocyte-specific Ppara deletion increases mitochondrial dysfunction-induced inflammation.
Fig. 8: Cardiomyocyte-specific Ppara deletion increased mitochondrial-dependent apoptosis.
Fig. 9: PPARα activation improves LPS-induced cardiac dysfunction and mitochondrial dysfunction.
Fig. 10: Cardiomyocyte PPARα protects against septic cardiac dysfunction by ameliorating mitochondrial dysfunction.

Similar content being viewed by others

References

  1. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 2018;392:75–87.

    Article  PubMed  Google Scholar 

  2. Lelubre C, Vincent JL. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 2018;14:417–27.

    Article  PubMed  Google Scholar 

  3. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med. 2019;51:162.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Picca A, Mankowski RT, Burman JL, Donisi L, Kim JS, Marzetti E, et al. Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol. 2018;15:543–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K. Molecular mechanisms and physiological functions of mitophagy. EMBO J. 2021;40:e104705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52.

    Article  CAS  PubMed  Google Scholar 

  7. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85–100.

    Article  CAS  PubMed  Google Scholar 

  8. Patoli D, Mignotte F, Deckert V, Dusuel A, Dumont A, Rieu A, et al. Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis. J Clin Invest. 2020;130:5858–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hussain T, Tan B, Yin Y, Blachier F, Tossou MC, Rahu N. Oxidative stress and inflammation: What polyphenols can do for us? Oxid Med Cell Longev. 2016;2016:7432797.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular Actions of PPARalpha in lipid metabolism and inflammation. Endocr Rev. 2018;39:760–802.

    Article  PubMed  Google Scholar 

  11. Barlaka E, Galatou E, Mellidis K, Ravingerova T, Lazou A. Role of pleiotropic properties of peroxisome proliferator-activated receptors in the heart: focus on the nonmetabolic effects in cardiac protection. Cardiovasc Ther. 2016;34:37–48.

    Article  CAS  PubMed  Google Scholar 

  12. Young ME, Laws FA, Goodwin GW, Taegtmeyer H. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem. 2001;276:44390–5.

    Article  CAS  PubMed  Google Scholar 

  13. Kaimoto S, Hoshino A, Ariyoshi M, Okawa Y, Tateishi S, Ono K, et al. Activation of PPAR-alpha in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. Am J Physiol Heart Circ Physiol. 2017;312:H305–H313.

    Article  PubMed  Google Scholar 

  14. Standage SW, Bennion BG, Knowles TO, Ledee DR, Portman MA, McGuire JK, et al. PPARalpha augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis. Am J Physiol Heart Circ Physiol. 2017;312:H239–H249.

    Article  PubMed  Google Scholar 

  15. Wang X, Zhu XX, Jiao SY, Qi D, Yu BQ, Xie GM, et al. Cardiomyocyte peroxisome proliferator-activated receptor alpha is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling. Acta Pharmacol Sin. 2022;43:1231–42.

    Article  CAS  PubMed  Google Scholar 

  16. Brocker CN, Yue J, Kim D, Qu A, Bonzo JA, Gonzalez FJ. Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells. Am J Physiol Gastrointest Liver Physiol. 2017;312:G283–G299.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhao H, Zhang M, Zhou F, Cao W, Bi L, Xie Y, et al. Cinnamaldehyde ameliorates LPS-induced cardiac dysfunction via TLR4-NOX4 pathway: The regulation of autophagy and ROS production. J Mol Cell Cardiol. 2016;101:11–24.

    Article  CAS  PubMed  Google Scholar 

  18. Qi D, Wei M, Jiao S, Song Y, Wang X, Xie G, et al. Hypoxia inducible factor 1alpha in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment. Cell Death Dis. 2019;10:544.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Busch K, Kny M, Huang N, Klassert TE, Stock M, Hahn A, et al. Inhibition of the NLRP3/IL-1beta axis protects against sepsis-induced cardiomyopathy. J Cachexia Sarcopenia Muscle. 2021;12:1653–68.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Li N, Zhou H, Wu H, Wu Q, Duan M, Deng W, et al. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol. 2019;24:101215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhagat A, Shrestha P, Kleinerman ES. The innate immune system in cardiovascular diseases and its role in doxorubicin-induced cardiotoxicity. Int J Mol Sci. 2022;23:14649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ouyang H, Li Q, Zhong J, Xia F, Zheng S, Lu J, et al. Combination of melatonin and irisin ameliorates lipopolysaccharide-induced cardiac dysfunction through suppressing the Mst1-JNK pathways. J Cell Physiol. 2020;235:6647–59.

    Article  CAS  PubMed  Google Scholar 

  23. Abate M, Festa A, Falco M, Lombardi A, Luce A, Grimaldi A, et al. Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol. 2020;98:139–53.

    Article  CAS  PubMed  Google Scholar 

  24. Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J Cachexia Sarcopenia Muscle. 2017;8:349–69.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wajner M, Amaral AU. Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies. Biosci Rep. 2015;36:e00281.

    Article  PubMed  Google Scholar 

  26. Shirihai OS, Song M, Dorn GW 2nd. How mitochondrial dynamism orchestrates mitophagy. Circ Res. 2015;116:1835–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun K, Jing X, Guo J, Yao X, Guo F. Mitophagy in degenerative joint diseases. Autophagy. 2021;17:2082–92.

    Article  CAS  PubMed  Google Scholar 

  28. Hu L, Huang B, Bai S, Tan J, Liu Y, Chen H, et al. SO2 derivatives induce dysfunction in human trophoblasts via inhibiting ROS/IL-6/STAT3 pathway. Ecotoxicol Environ Saf. 2021;210:111872.

    Article  CAS  PubMed  Google Scholar 

  29. Zanders L, Kny M, Hahn A, Schmidt S, Wundersitz S, Todiras M, et al. Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting. J Cachexia Sarcopenia Muscle. 2022;13:713–27.

    Article  PubMed  Google Scholar 

  30. Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell. 2011;21:92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol. 2021;18:809–23.

    Article  CAS  PubMed  Google Scholar 

  32. Standage SW, Waworuntu RL, Delaney MA, Maskal SM, Bennion BG, Duffield JS, et al. Nonhematopoietic peroxisome proliferator-activated receptor-alpha protects against cardiac injury and enhances survival in experimental polymicrobial sepsis. Crit Care Med. 2016;44:e594–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Makrecka-Kuka M, Korzh S, Vilks K, Vilskersts R, Cirule H, Dambrova M, et al. Mitochondrial function in the kidney and heart, but not the brain, is mainly altered in an experimental model of endotoxaemia. Shock. 2019;52:e153–e162.

    Article  CAS  PubMed  Google Scholar 

  34. Chan DC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol. 2020;15:235–59.

    Article  CAS  PubMed  Google Scholar 

  35. Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 2020;21:204–24.

    Article  CAS  PubMed  Google Scholar 

  36. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res. 2021;128:1487–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88:611–38.

    Article  CAS  PubMed  Google Scholar 

  38. Chen M, Chen Z, Wang Y, Tan Z, Zhu C, Li Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy. 2016;12:689–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Doblado L, Lueck C, Rey C, Samhan-Arias AK, Prieto I, Stacchiotti A, et al. Mitophagy in human diseases. Int J Mol Sci. 2021;22:3903.

    Article  Google Scholar 

  40. Feng Y, Madungwe NB, da Cruz Junho CV, Bopassa JC. Activation of G protein-coupled oestrogen receptor 1 at the onset of reperfusion protects the myocardium against ischemia/reperfusion injury by reducing mitochondrial dysfunction and mitophagy. Br J Pharmacol. 2017;174:4329–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nguyen TN, Padman BS, Lazarou M. Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol. 2016;26:733–44.

    Article  CAS  PubMed  Google Scholar 

  42. Miller S, Oleksy A, Perisic O, Williams RL. Finding a fitting shoe for Cinderella: Searching for an autophagy inhibitor. Autophagy. 2010;6:805–7.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Drosatos K, Khan RS, Trent CM, Jiang H, Son NH, Blaner WS, et al. Peroxisome proliferator-activated receptor-gamma activation prevents sepsis-related cardiac dysfunction and mortality in mice. Circ Heart Fail. 2013;6:550–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by National Key R&D Program of China (2021YFA0805100), National Natural Science Foundation of China (82070474), Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (CIT&TCD20190332), The Key Science and Technology Project of Beijing Municipal Institutions (KZ202010025032) to AJQ, National Natural Science Foundation of China (81800233) to XW. and the National Cancer Institute Intramural Research Program to FJG.

Author information

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education; Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, 100069, China

    Xin-xin Zhu, Xia Wang, Shi-yu Jiao, Ye Liu, Li Shi, Yun-er Chen, Qi Zhang, Ming Wei, Bao-qi Yu, Jie Du & Ai-juan Qu

  2. Core Facility Centre, Capital Medical University, Beijing, 100069, China

    Qing Xu

  3. Department of Laboratory Animal Capital Medical University, Beijing, 100069, China

    Jing-jing Wang

  4. Department of Pathology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China

    Yan-ting Song

  5. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Mecklenburg-Vorpommern, Germany

    Jens Fielitz

  6. Department of Internal Medicine B, Cardiology, University Medicine Greifswald, Mecklenburg-Vorpommern, Germany

    Jens Fielitz

  7. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Frank J. Gonzalez

  8. Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China

    Jie Du

Authors
  1. Xin-xin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shi-yu Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ye Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing-jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yun-er Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan-ting Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ming Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bao-qi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jens Fielitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Frank J. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jie Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ai-juan Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XXZ designed the study, performed the experiments, and wrote the manuscript. XW, SYJ, YL, LS, YEC, QZ, YTS, and MW performed the experiments and analyzed the data. QX participated in the echocardiography. JJW was in charge of mice. JD and BQY participated in the initial elaboration of the project. JF provided transcription data and involved in writing the manuscript. FJG designed the experimental plan, supervised the study and involved in writing the manuscript. AJQ conceived, supervised the study, and wrote the manuscript. All authors read and edited the manuscript.

Corresponding author

Correspondence to Ai-juan Qu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Xx., Wang, X., Jiao, Sy. et al. Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function. Acta Pharmacol Sin 44, 2184–2200 (2023). https://doi.org/10.1038/s41401-023-01107-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01107-5

Keywords

Search

Advanced search

Quick links