Vol 61, No 1 (2023)
Original paper
Published online: 2023-03-06

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HDAC6 inhibition alleviates acute pulmonary embolism: a possible future therapeutic option

Tao Zhou1, Di Jia2, Jiahui Han2, Ce Xu2, Xiaohong You1, Xin Ge23
Pubmed: 36880683
Folia Histochem Cytobiol 2023;61(1):56-67.

Abstract

Introduction. Acute pulmonary embolism (APE) is a clinical syndrome of pulmonary circulation disorder caused by obstruction of the pulmonary artery or its branches. Histone deacetylase 6 (HDAC6) has been reported to play an important role in lung-related diseases. However, the functional role of HDAC6 in APE remains unclear.

Material and methods. Male Sprague Dawley rats were used. The APE model was constructed by inserting an intravenous cannula into the right femoral vein and injecting Sephadex G-50 microspheres (12 mg/kg; 300 μm in diameter). After 1 h, the control and APE rats were intraperitoneally injected with tubastatin A (TubA) (40 mg/kg, an inhibitor of HDAC6) and sampled at 24 h after modeling. H&E staining, arterial blood gas analysis, and wet/dry (W/D) weight ratio were used to evaluate the histopathological changes and pulmonary function in APE rats. ELISA, Western blot, and immunohistochemistry were used to explore the potential mechanism of HDAC6-mediated inflammation in APE.

Results. The results indicated that HDAC6 expression was significantly increased in lungs of APE rats. TubA treatment in vivo decreased HDAC6 expression in lung tissues. HDAC6 inhibition alleviated histopathological damage and pulmonary dysfunction, as evidenced by decreased PaO2/FiO2 ratio and W/D weight ratio in APE rats. Furthermore, HDAC6 inhibition alleviated APE-induced inflammatory response. Specifically, APE rats exhibited increased production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-18, however, this increase was reversed by HDAC6 inhibition. Meanwhile, the activation of the NLRP3 inflammasome was also observed in lungs of APE rats, while HDAC6 inhibition blocked this activation. Mechanically, we demonstrated that HDAC6 inhibition blocked the activation of the protein kinase B (AKT)/extracellular signal-regulated protein kinase (ERK) signaling pathway, a classic pathway promoting inflammation.

Conclusions. These findings demonstrate that the inhibition of HDAC6 may alleviate lung dysfunction and pathological injury resulting from APE by blocking the AKT/ERK signaling pathway, providing new theoretical fundamentals for APE therapy.

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References

  1. Gervaise A, Bouzad C, Peroux E, et al. Acute pulmonary embolism in non-hospitalized COVID-19 patients referred to CTPA by emergency department. Eur Radiol. 2020; 30(11): 6170–6177.
  2. Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet. 2016; 388(10063): 3060–3073.
  3. Zhang J, Xu Y, Wu Y, et al. Nursing care for a patient with right frontoparietal inflammatory granuloma complicated with acute pulmonary embolism: a case report. Ann Palliat Med. 2020; 9(5): 3643–3650.
  4. Riedel M. Acute pulmonary embolism 1: pathophysiology, clinical presentation, and diagnosis. Heart. 2001; 85(2): 229–240.
  5. Martinez Licha CR, McCurdy CM, Maldonado SM, et al. Current management of acute pulmonary embolism. Ann Thorac Cardiovasc Surg. 2020; 26(2): 65–71.
  6. Demelo-Rodriguez P, Galeano-Valle F, Salzano A, et al. Pulmonary embolism: a practical guide for the busy clinician. Heart Fail Clin. 2020; 16(3): 317–330.
  7. Zuo Z, Yue J, Dong BiR, et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2021; 4(4): CD004437.
  8. LeVarge BL, Wright CD, Rodriguez-Lopez JM. Surgical management of acute and chronic pulmonary embolism. Clin Chest Med. 2018; 39(3): 659–667.
  9. Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002; 417(6887): 455–458.
  10. Ferreira de Freitas R, Harding RJ, Franzoni I, et al. Identification and structure-activity relationship of HDAC6 zinc-finger ubiquitin binding domain inhibitors. J Med Chem. 2018; 61(10): 4517–4527.
  11. Song R, Yang Y, Lei H, et al. HDAC6 inhibition protects cardiomyocytes against doxorubicin-induced acute damage by improving α-tubulin acetylation. J Mol Cell Cardiol. 2018; 124: 58–69.
  12. Lin CF, Hsu KC, HuangFu WC, et al. Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury. BMC Pharmacol Toxicol. 2020; 21(1): 21.
  13. Leng Y, Wu Y, Lei S, et al. Inhibition of HDAC6 activity alleviates myocardial ischemia/reperfusion injury in diabetic rats: potential role of peroxiredoxin 1 acetylation and redox regulation. Oxid Med Cell Longev. 2018; 2018: 9494052.
  14. Chi Z, Le TP, Lee SKi, et al. Honokiol ameliorates angiotensin II-induced hypertension and endothelial dysfunction by inhibiting HDAC6-mediated cystathionine γ-lyase degradation. J Cell Mol Med. 2020; 24(18): 10663–10676.
  15. Allende M, Molina E, Lecumberri R, et al. Inducing heat shock protein 70 expression provides a robust antithrombotic effect with minimal bleeding risk. Thromb Haemost. 2017; 117(9): 1722–1729.
  16. Liu Li, Zhou X, Shetty S, et al. HDAC6 inhibition blocks inflammatory signaling and caspase-1 activation in LPS-induced acute lung injury. Toxicol Appl Pharmacol. 2019; 370: 178–183.
  17. Youn GiS, Lee KW, Choi SY, et al. Overexpression of HDAC6 induces pro-inflammatory responses by regulating ROS-MAPK-NF-κB/AP-1 signaling pathways in macrophages. Free Radic Biol Med. 2016; 97: 14–23.
  18. Zhang WB, Yang F, Wang Y, et al. Inhibition of HDAC6 attenuates LPS-induced inflammation in macrophages by regulating oxidative stress and suppressing the TLR4-MAPK/NF-κB pathways. Biomed Pharmacother. 2019; 117: 109166.
  19. Butler KV, Kalin J, Brochier C, et al. Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc. 2010; 132(31): 10842–10846.
  20. Chen J, Liu S, Wang X, et al. HDAC6 inhibition alleviates anesthesia and surgery-induced less medial prefrontal-dorsal hippocampus connectivity and cognitive impairment in aged rats. Mol Neurobiol. 2022; 59(10): 6158–6169.
  21. Yu J, Ma Z, Shetty S, et al. Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Am J Physiol Lung Cell Mol Physiol. 2016; 311(1): L39–L47.
  22. Joshi AD, Barabutis N, Birmpas C, et al. Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function. Am J Physiol Lung Cell Mol Physiol. 2015; 309(12): L1410–L1419.
  23. Boucherat O, Chabot S, Paulin R, et al. HDAC6: a novel histone deacetylase implicated in pulmonary arterial hypertension. Sci Rep. 2017; 7(1): 4546.
  24. Lu G, Jia Z, Zu Q, et al. Inhibition of the cyclophilin A-CD147 interaction attenuates right ventricular injury and dysfunction after acute pulmonary embolism in rats. J Biol Chem. 2018; 293(31): 12199–12208.
  25. Zagorski J, Debelak J, Gellar M, et al. Chemokines accumulate in the lungs of rats with severe pulmonary embolism induced by polystyrene microspheres. J Immunol. 2003; 171(10): 5529–5536.
  26. Feng W, Wang J, Yan X, et al. ERK/Drp1-dependent mitochondrial fission contributes to HMGB1-induced autophagy in pulmonary arterial hypertension. Cell Prolif. 2021; 54(6): e13048.
  27. Liu Z, Chen J, Hu La, et al. Expression profiles of genes associated with inflammatory responses and oxidative stress in lung after heat stroke. Biosci Rep. 2020; 40(6).
  28. Zhang P, Zhang Y, Wang Lu, et al. Reversal of NADPH oxidase-dependent early oxidative and inflammatory responses in chronic obstructive pulmonary disease by puerarin. Oxid Med Cell Longev. 2022; 2022: 5595781.
  29. Niu F, Li H, Xu X, et al. Ursodeoxycholic acid protects against lung injury induced by fat embolism syndrome. J Cell Mol Med. 2020; 24(24): 14626–14632.
  30. Yang X, An X, Wang C, et al. Protective effect of oxytocin on ventilator-induced lung injury through NLRP3-mediated pathways. Front Pharmacol. 2021; 12: 722907.
  31. Hobohm L, Becattini C, Konstantinides SV, et al. Validation of a fast prognostic score for risk stratification of normotensive patients with acute pulmonary embolism. Clin Res Cardiol. 2020; 109(8): 1008–1017.
  32. Karki P, Ke Y, Tian Y, et al. Staphylococcus aureus-induced endothelial permeability and inflammation are mediated by microtubule destabilization. J Biol Chem. 2019; 294(10): 3369–3384.
  33. Klok FA, Ageno W, Ay C, et al. Optimal follow-up after acute pulmonary embolism: a position paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, endorsed by the European Respiratory Society. Eur Heart J. 2022; 43(3): 183–189.
  34. Lkhagva B, Lin YK, Kao YH, et al. Novel histone deacetylase inhibitor modulates cardiac peroxisome proliferator-activated receptors and inflammatory cytokines in heart failure. Pharmacology. 2015; 96(3-4): 184–191.
  35. Li M, Hu W, Wang R, et al. Sp1 s-sulfhydration induced by hydrogen sulfide inhibits inflammation via HDAC6/myd88/nf-κb signaling pathway in adjuvant-induced arthritis. Antioxidants (Basel). 2022; 11(4).
  36. Kwon Y, Choi Y, Kim M, et al. HDAC6 and CXCL13 mediate atopic dermatitis by regulating cellular interactions and expression levels of miR-9 and SIRT1. Front Pharmacol. 2021; 12: 691279.
  37. Biersack B, Nitzsche B, Höpfner M. Immunomodulatory properties of HDAC6 inhibitors in cancer diseases: new chances for sophisticated drug design and treatment optimization. Semin Cell Dev Biol. 2022 [Epub ahead of print].
  38. Song Y, Zhang H, Yang X, et al. Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021. Eur J Med Chem. 2022; 228: 114042.
  39. Pulya S, Amin SkA, Adhikari N, et al. HDAC6 as privileged target in drug discovery: a perspective. Pharmacol Res. 2021; 163: 105274.
  40. Li Y, Sang S, Ren W, et al. Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010-2020). Eur J Med Chem. 2021; 226: 113874.
  41. Deng Q, Zhao T, Pan B, et al. Protective effect of tubastatin a in CLP-induced lethal sepsis. Inflammation. 2018; 41(6): 2101–2109.
  42. Cloonan SM, Lam HC, Ryter SW, et al. "Ciliophagy": The consumption of cilia components by autophagy. Autophagy. 2014; 10(3): 532–534.
  43. Song Y, Jiang Y, Tao D, et al. NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma. Neuro Oncol. 2020; 22(1): 46–57.
  44. Yao F, Jin Z, Zheng Z, et al. HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells. Cell Death Discov. 2022; 8(1): 112.
  45. Mansini AP, Lorenzo Pisarello MJ, Thelen KM, et al. MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma. Hepatology. 2018; 68(2): 561–573.
  46. Sharma P, Caldwell TS, Rivera MN, et al. Cadmium exposure activates Akt/ERK Signaling and pro-inflammatory COX-2 expression in human gallbladder epithelial cells via a ROS dependent mechanism. Toxicol In Vitro. 2020; 67: 104912.
  47. Wang L, Wu J, Zhang W, et al. Effects of aspirin on the ERK and PI3K/Akt signaling pathways in rats with acute pulmonary embolism. Mol Med Rep. 2013; 8(5): 1465–1471.
  48. Yan G, Wang J, Yi T, et al. Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways. Pulm Circ. 2019; 9(4): 2045894019878599.
  49. Kim DIm, Song MK, Lee K. Diesel exhaust particulates enhances susceptibility of LPS-induced acute lung injury through upregulation of the IL-17 cytokine-derived TGF-β/collagen i expression and activation of NLRP3 inflammasome signaling in mice. Biomolecules. 2021; 11(1).
  50. Nava P, Koch S, Laukoetter MG, et al. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity. 2010; 32(3): 392–402.
  51. Yang W, Yan A, Zhang T, et al. Thromboxane A2 receptor stimulation enhances microglial interleukin-1β and NO biosynthesis mediated by the activation of ERK pathway. Front Aging Neurosci. 2016; 8: 8.