Skip to main content

Advertisement

SpringerLink
Log in

Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan, has been proven to fulfill an essential function in cardiovascular disease (CVD) and nerve regeneration disease. However, the role of IPA in aortic dissection (AD) has not been revealed. We aimed to investigate the role of IPA in the pathogenesis of AD and the underlying mechanisms of IPA in endothelial dysfunction. Untargeted metabolomics has been employed to screen the plasma metabolic profile of AD patients in comparison with healthy individuals. Network pharmacology provides insights into the potential molecular mechanisms underlying IPA. 3-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang II) were administered to induce AD in mice, while human umbilical vein endothelial cells (HUVECs) were employed for in vitro validation of the signaling pathways predicted by network pharmacology. A total of 224 potentially differential plasma metabolites were identified in the AD patients, with 110 up-regulated metabolites and 114 down-regulated metabolites. IPA was the most significantly decreased metabolite involved in tryptophan metabolism. Bcl2, caspase3, and AKT1 were predicted as the target genes of IPA by network pharmacology and molecular docking. IPA suppressed Ang II-induced apoptosis, intracellular ROS generation, inflammation, and endothelial tight junction (TJ) loss. Animal experiments demonstrated that administration of IPA alleviated the occurrence and severity of AD in mice. Taken together, we identified a previously unexplored association between tryptophan metabolite IPA and AD, providing a novel perspective on the underlying mechanism through which IPA mitigates endothelial dysfunction to protect against AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to relevant ongoing research but are available from the corresponding author on reasonable request.

References

  1. Zhu Y, Lingala B, Baiocchi M, Tao JJ, Toro Arana V, Khoo JW et al (2020) Type A aortic dissection-experience over 5 decades: JACC historical breakthroughs in perspective. J Am Coll Cardiol 76:1703–1713

    Article  PubMed  Google Scholar 

  2. Isselbacher EM, Preventza O, Hamilton Black 3rd J, Augoustides JG, Beck AW, Bolen MA et al (2022) 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 146:e334–e482

    Article  PubMed  Google Scholar 

  3. Bai B, Yang Y, Wang Q, Li M, Tian C, Liu Y et al (2020) NLRP3 inflammasome in endothelial dysfunction. Cell Death Dis 11:776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yang X, Xu C, Yao F, Ding Q, Liu H, Luo C et al (2023) Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection. Eur Heart J 44:1248–1261

    Article  CAS  PubMed  Google Scholar 

  5. Folkersen L, Gustafsson S, Wang Q, Hansen DH (2020) Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metab 2:1135–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cui H, Chen Y, Li K, Zhan R, Zhao M, Xu Y et al (2021) Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection. Eur Heart J 42:4373–4385

    Article  CAS  PubMed  Google Scholar 

  7. Lieberg J, Wanhainen A, Ottas A, Vähi M, Zilmer M, Soomets U et al (2021) Metabolomic profile of abdominal aortic aneurysm. Metabolites. https://doi.org/10.3390/metabo11080555

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yang Y, Karampoor S, Mirzaei R, Borozdkin L, Zhu P (2023) The interplay between microbial metabolites and macrophages in cardiovascular diseases: a comprehensive review. Int Immunopharmacol 121:110546

    Article  CAS  PubMed  Google Scholar 

  9. Hwang IK, Yoo KY, Li H, Park OK, Lee CH, Choi JH et al (2009) Indole-3-propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. J Neurosci Res 87:2126–2137

    Article  CAS  PubMed  Google Scholar 

  10. Kwun MS, Lee DG (2021) Investigation of distinct contribution of nitric oxide and each reactive oxygen species in indole-3-propionic-acid-induced apoptosis-like death in Escherichia coli. Life Sci 285:120003

    Article  CAS  PubMed  Google Scholar 

  11. Rothhammer V, Mascanfroni ID, Bunse L (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao ZH, Xin FZ, Xue Y, Hu Z, Han Y, Ma F et al (2019) Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats. Exp Mol Med 51:1–14

    PubMed  PubMed Central  Google Scholar 

  13. Xie Y, Zou X, Han J, Zhang Z, Feng Z, Ouyang Q et al (2022) Indole-3-propionic acid alleviates ischemic brain injury in a mouse middle cerebral artery occlusion model. Exp Neurol 353:114081

    Article  CAS  PubMed  Google Scholar 

  14. Krug D, Zurek G, Schneider B, Garcia R, Müller R (2008) Efficient mining of myxobacterial metabolite profiles enabled by liquid chromatography-electrospray ionisation-time-of-flight mass spectrometry and compound-based principal component analysis. Anal Chim Acta 624:97–106

    Article  CAS  PubMed  Google Scholar 

  15. Wang Q, Yesitayi G, Liu B, Siti D, Ainiwan M, Aizitiaili A et al (2023) Targeting metabolism in aortic aneurysm and dissection: from basic research to clinical applications. Int J Biol Sci 19:3869–3891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang J, Li Y, Lu Z, Che Y, Sun S, Mao S et al (2019) Analysis of functional hub genes identifies CDC45 as an oncogene in non-small cell lung cancer—a short report. Cell Oncol (Dordr) 42:571–578

    Article  CAS  PubMed  Google Scholar 

  17. Nicolini G, Forini F, Kusmic C, Iervasi G, Balzan S (2019) Angiopoietin 2 signal complexity in cardiovascular disease and cancer. Life Sci 239:117080

    Article  CAS  PubMed  Google Scholar 

  18. Pan L, Lin Z, Tang X, Tian J, Zheng Q, Jing J et al (2020) S-Nitrosylation of plastin-3 exacerbates thoracic aortic dissection formation via endothelial barrier dysfunction. Arterioscler Thromb Vasc Biol 40:175–188

    Article  CAS  PubMed  Google Scholar 

  19. Jones DT, Ganeshaguru K, Anderson RJ, Jackson TR, Bruckdorfer KR, Low SY et al (2003) Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis. Blood 101:3174–3180

    Article  CAS  PubMed  Google Scholar 

  20. Melgar-Lesmes P, Tugues S, Ros J, Fernández-Varo G, Morales-Ruiz M, Rodés J et al (2009) Vascular endothelial growth factor and angiopoietin-2 play a major role in the pathogenesis of vascular leakage in cirrhotic rats. Gut 58:285–292

    Article  CAS  PubMed  Google Scholar 

  21. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  ADS  CAS  PubMed  Google Scholar 

  22. König T, Nolte H, Aaltonen MJ (2021) MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat Cell Biol 23:1271–1286

    Article  PubMed  Google Scholar 

  23. Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L et al (2018) Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. Autophagy 14:845–861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xue M, Minhas N, Chow SO, Dervish S, Sambrook PN, March L et al (2010) Endogenous protein C is essential for the functional integrity of human endothelial cells. Cell Mol Life Sci 67:1537–1546

    Article  CAS  PubMed  Google Scholar 

  25. Witkowski M, Weeks TL, Hazen SL (2020) Gut microbiota and cardiovascular disease. Circ Res 127:553–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Q, Ding Y, Song P, Zhu H, Okon I, Ding YN et al (2017) Tryptophan-derived 3-hydroxyanthranilic acid contributes to angiotensin ii-induced abdominal aortic aneurysm formation in mice in vivo. Circulation 136:2271–2283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li Q, You Y, Zeng Y, Wang X, Pan Z, Pang J et al (2022) Associations between plasma tryptophan and indole-3-propionic acid levels and mortality in patients with coronary artery disease. Am J Clin Nutr 116:1070–1077

    Article  PubMed  Google Scholar 

  28. Xue H, Chen X, Yu C, Deng Y, Zhang Y, Chen S (2022) Gut microbially produced indole-3-propionic acid inhibits atherosclerosis by promoting reverse cholesterol transport and its deficiency is causally related to atherosclerotic cardiovascular disease. Circ Res 131:404–420

    Article  CAS  PubMed  Google Scholar 

  29. Kim C-S, Jung S, Hwang G-S, Shin D-M (2023) Gut microbiota indole-3-propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: a randomized, double-blind, placebo-controlled, multicenter trial and in vitro study. Clin Nutr 42:1025–1033

    Article  CAS  PubMed  Google Scholar 

  30. Nienaber CA, Clough RE, Sakalihasan N, Suzuki T, Gibbs R, Mussa F et al (2016) Aortic dissection. Nat Rev Disease Prim 2:16053

    Article  Google Scholar 

  31. Chakraborty A, Li Y, Zhang C, Li Y, Lemaire SA, Shen YH (2022) Programmed cell death in aortic aneurysm and dissection: a potential therapeutic target. J Mol Cell Cardiol 163:67–80

    Article  CAS  PubMed  Google Scholar 

  32. Carrel T, Sundt 3rd TM, Von Kodolitsch Y, Czerny M (2023) Acute aortic dissection. Lancet 401:773–788

    Article  PubMed  Google Scholar 

  33. Rombouts KB (2022) Van Merrienboer TAR, Ket JCF, Bogunovic N The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections. Eur J Clin Investig 52:e13697

    Article  CAS  Google Scholar 

  34. Zhang Y, Song Z, Huang S, Zhu L, Liu T, Shu H et al (2020) Aloe emodin relieves Ang II-induced endothelial junction dysfunction via promoting ubiquitination mediated NLRP3 inflammasome inactivation. J Leucocyte Biol 108:1735–1746

    Article  CAS  Google Scholar 

  35. Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115:1285–1295

    Article  PubMed  Google Scholar 

  36. Oduro PK, Zheng X, Wei J, Yang Y, Wang Y, Zhang H et al (2022) The cGAS-STING signaling in cardiovascular and metabolic diseases: future novel target option for pharmacotherapy. Acta Pharm Sin B 12:50–75

    Article  CAS  PubMed  Google Scholar 

  37. Duan MX, Zhou H (2019) Andrographolide protects against HG-induced inflammation, apoptosis, migration, and impairment of angiogenesis via PI3K/AKT-eNOS signalling in HUVECs. Mediat Inflamm 2019:6168340

    Article  Google Scholar 

  38. Li J, Chen Q, He X, Alam A, Ning J, Yi B et al (2018) Dexmedetomidine attenuates lung apoptosis induced by renal ischemia-reperfusion injury through α(2)AR/PI3K/Akt pathway. J Transl Med 16:78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lin HK, Yeh S, Kang HY, Chang C (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA 98:7200–7205

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Konopelski P, Mogilnicka I (2022) Biological effects of indole-3-propionic acid, a gut microbiota-derived metabolite, and its precursor tryptophan in mammals’ health and disease. Int J Mol Sci 23:1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang LS, Davies SS (2016) Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med 8:46

    Article  PubMed  PubMed Central  Google Scholar 

  42. Garcez ML, Tan VX, Heng B (2020) Sodium butyrate and indole-3-propionic acid prevent the increase of cytokines and kynurenine levels in LPS-induced human primary astrocytes. Int J Tryptophan Res 13:1178646920978404

    Article  PubMed  PubMed Central  Google Scholar 

  43. Du L, Qi R, Wang J, Liu Z, Wu Z (2021) Indole-3-propionic acid, a functional metabolite of clostridium sporogenes, promotes muscle tissue development and reduces muscle cell inflammation. Int J Mol Sci 22:12435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y et al (2021) Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics 11:1845–1863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Su X, Gao Y, Yang R (2022) Gut microbiota-derived tryptophan metabolites maintain gut and systemic homeostasis. Cells 11:2296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhao Q, Chen T, Ni C, Hu Y, Nan Y, Lin W et al (2022) Indole-3-propionic acid attenuates HI-related blood-brain barrier injury in neonatal rats by modulating the PXR signaling pathway. ACS Chem Neurosci 13:2897–2912

    Article  CAS  PubMed  Google Scholar 

  47. Perler BK, Friedman ES, Wu GD (2023) The role of the gut microbiota in the relationship between diet and human health. Annu Rev Physiol 85:449–468

    Article  CAS  PubMed  Google Scholar 

  48. Li J, Zhang L, Wu T, Li Y, Zhou X, Ruan Z (2021) Indole-3-propionic acid improved the intestinal barrier by enhancing epithelial barrier and mucus barrier. J Agric Food Chem 69:1487–1495

    Article  CAS  PubMed  Google Scholar 

  49. Konopelski P, Chabowski D, Aleksandrowicz M (2021) Indole-3-propionic acid, a tryptophan-derived bacterial metabolite, increases blood pressure via cardiac and vascular mechanisms in rats. Am J Physiol Regul Integr Compar Physiol 321:R969–R981

    Article  CAS  Google Scholar 

  50. Liu F, Sun C, Chen Y, Du F, Yang Y, Wu G (2021) Indole-3-propionic acid-aggravated CCl(4)-induced liver fibrosis via the TGF-β1/Smads signaling pathway. J Clin Transl Hepatol 9:917–930

    PubMed  PubMed Central  Google Scholar 

  51. Serger E, Luengo-Gutierrez L (2022) The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature 607:585–592

    Article  ADS  CAS  PubMed  Google Scholar 

Download references

Funding

This work was funded by the Sponsored by Natural Science Foundation of Xinjiang Uygur Autonomous Region (No. 2022D01D66), National Natural Science Foundation of China (No. 82360090), State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia Fund (SKL-HIDCA-2021-3), and Postgraduate Research Innovation Project of Xinjiang Uygur Autonomous Region (No. XJ2023G158).

Author information

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Ürümqi, China

    Qi Wang, Hui Lv, Mierxiati Ainiwan, Gulinazi Yesitayi, Asiya Abudesimu, Dilixiati Siti, Aliya Aizitiaili & Xiang Ma

  2. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China

    Xiang Ma

Authors
  1. Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mierxiati Ainiwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gulinazi Yesitayi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asiya Abudesimu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dilixiati Siti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aliya Aizitiaili
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, Qi Wang and Xiang Ma; Data curation, Mierxiati Ainiwan; Investigation, Aliya Aizitiaili; Methodology, Hui Lv, Gulinazi Yesitayi and Asiya Abudesimu; Supervision, Qi Wang and Xiang Ma; Validation, Hui Lv, Mierxiati Ainiwan, Gulinazi Yesitayi and Dilixiati Siti; Writing—original draft, Qi Wang; Writing—review and editing, Qi Wang and Xiang Ma.

Corresponding author

Correspondence to Xiang Ma.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The study was conducted in accordance with the Declaration of Helsinki, and approved by the Medical Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (230306-88). The animal study protocol was approved by the Animal Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University. We confirmed that all methods were carried out in accordance with relevant regulations and informed consent was obtained from patients.

Informed consent

Informed consent was obtained from all subjects involved in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 505 kb)

Supplementary file2 (DOCX 19 kb)

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

Wang, Q., Lv, H., Ainiwan, M. et al. Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04961-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-024-04961-x

Keywords

Search

Navigation