PKG1 promotes the HIV-induced proliferation, migration, and fibrosis of vascular smooth muscle cells of hemorrhoids.
CGMP-dependent protein kinase 1
Fibrosis
Hemorrhoids
Human immunodeficiency virus
Vascular smooth muscle cells
Journal
International journal of colorectal disease
ISSN: 1432-1262
Titre abrégé: Int J Colorectal Dis
Pays: Germany
ID NLM: 8607899
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
accepted:
12
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Hemorrhoids are very common in patients with human immunodeficiency virus (HIV) infection. The risk of postoperative infection is significantly greater in HIV-positive patients than in HIV-negative individuals, and the wound healing time is significantly prolonged. This study aimed to investigate the role of HIV-associated hemorrhoids from the perspective of vascular smooth muscle cell (VSMC) function. A total of 24 hemorrhoid tissue samples (note: grade IV hemorrhoids were absence) were collected and subjected to Masson staining to evaluate fibrosis in this study. mRNA and protein levels were monitored by qPCR and WB analysis, respectively. Immunofluorescence was conducted to evaluate PKG1 and α-SMA expression. To establish a cell model in vitro, VSMCs were stimulated with envelope glycoprotein (gp) 120, which is a type of HIV envelope protein. Cell proliferation was assessed via a CCK-8 assay and EdU staining. Moreover, a wound healing assay was performed to assess cell migration. Our data confirmed that fibrosis was present in hemorrhoid tissues from HIV-infected patients and that PKG1 expression was upregulated. Moreover, the administration of HIV gp120 promoted the proliferation and migration of VSMCs. Similarly, fibrosis-related markers (α-SMA, MMP2, MMP3, and TIMP1) were markedly upregulated. However, silencing PKG1 inhibited the proliferation, migration, and expression of fibrosis-related markers in gp120-challenged VSMCs. The present research revealed that PKG1 regulated the proliferation, migration, and fibrosis of VSMCs, thereby exerting detrimental effects on HIV-associated hemorrhoids.
Sections du résumé
BACKGROUND
BACKGROUND
Hemorrhoids are very common in patients with human immunodeficiency virus (HIV) infection. The risk of postoperative infection is significantly greater in HIV-positive patients than in HIV-negative individuals, and the wound healing time is significantly prolonged. This study aimed to investigate the role of HIV-associated hemorrhoids from the perspective of vascular smooth muscle cell (VSMC) function.
METHODS
METHODS
A total of 24 hemorrhoid tissue samples (note: grade IV hemorrhoids were absence) were collected and subjected to Masson staining to evaluate fibrosis in this study. mRNA and protein levels were monitored by qPCR and WB analysis, respectively. Immunofluorescence was conducted to evaluate PKG1 and α-SMA expression. To establish a cell model in vitro, VSMCs were stimulated with envelope glycoprotein (gp) 120, which is a type of HIV envelope protein. Cell proliferation was assessed via a CCK-8 assay and EdU staining. Moreover, a wound healing assay was performed to assess cell migration.
RESULTS
RESULTS
Our data confirmed that fibrosis was present in hemorrhoid tissues from HIV-infected patients and that PKG1 expression was upregulated. Moreover, the administration of HIV gp120 promoted the proliferation and migration of VSMCs. Similarly, fibrosis-related markers (α-SMA, MMP2, MMP3, and TIMP1) were markedly upregulated. However, silencing PKG1 inhibited the proliferation, migration, and expression of fibrosis-related markers in gp120-challenged VSMCs.
CONCLUSION
CONCLUSIONS
The present research revealed that PKG1 regulated the proliferation, migration, and fibrosis of VSMCs, thereby exerting detrimental effects on HIV-associated hemorrhoids.
Identifiants
pubmed: 39477875
doi: 10.1007/s00384-024-04743-3
pii: 10.1007/s00384-024-04743-3
doi:
Substances chimiques
Cyclic GMP-Dependent Protein Kinase Type I
EC 2.7.11.12
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
175Subventions
Organisme : Research Project of Health Commission of Hunan Province
ID : No. 202201042974
Organisme : Research Project of Health Commission of Hunan Province
ID : No. 202201042974
Organisme : Research Project of Health Commission of Hunan Province
ID : No. 202201042974
Organisme : Research Project of Health Commission of Hunan Province
ID : No. 202201042974
Organisme : Research Project of Health Commission of Hunan Province
ID : No. 202201042974
Organisme : Hunan Natural Science Foundation
ID : No. 2023JJ60391
Organisme : Hunan Natural Science Foundation
ID : No. 2023JJ60391
Organisme : Hunan Natural Science Foundation
ID : No. 2023JJ60391
Organisme : Hunan Natural Science Foundation
ID : No. 2023JJ60391
Organisme : Hunan Natural Science Foundation
ID : No. 2023JJ60391
Organisme : Science Foundation of Changsha Science and Technology Project
ID : No. kq2004157
Organisme : Science Foundation of Changsha Science and Technology Project
ID : No. kq2004157
Organisme : Science Foundation of Changsha Science and Technology Project
ID : No. kq2004157
Organisme : Science Foundation of Changsha Science and Technology Project
ID : No. kq2004157
Organisme : Science Foundation of Changsha Science and Technology Project
ID : No. kq2004157
Organisme : Science Foundation of First Hospital of Changsha
ID : No. Y2022-17
Organisme : Science Foundation of First Hospital of Changsha
ID : No. Y2022-17
Organisme : Science Foundation of First Hospital of Changsha
ID : No. Y2022-17
Organisme : Science Foundation of First Hospital of Changsha
ID : No. Y2022-17
Organisme : Science Foundation of First Hospital of Changsha
ID : No. Y2022-17
Informations de copyright
© 2024. The Author(s).
Références
Pines H, Wertheim J, Liu L, Garfein R, Little S, Karris MJA (2016) Concurrency and HIV transmission network characteristics among MSM with recent HIV infection. Aids 30(18):2875–83. https://doi.org/10.1097/qad.0000000000001256
doi: 10.1097/qad.0000000000001256
pubmed: 27662550
Solomon S, Solomon S, McFall A, Srikrishnan A, Anand S, Verma V et al (2019) Integrated HIV testing, prevention, and treatment intervention for key populations in India: a cluster-randomised trial. Lancet HIV 6(5):e283–e96. https://doi.org/10.1016/s2352-3018(19)30034-7
doi: 10.1016/s2352-3018(19)30034-7
pubmed: 30952565
pmcid: 6524776
Zhou J, Yang L, Ma J, Jiang S, Liu Y, Sun Z (2022) Factors associated with HIV testing among MSM in Guilin, China: results from a cross-sectional study. Int J Public Health 67:1604612. https://doi.org/10.3389/ijph.2022.1604612
doi: 10.3389/ijph.2022.1604612
pubmed: 35936995
pmcid: 9346121
Arias Garcia S, Chen J, Calleja J, Sabin K, Ogbuanu C, Lowrance D et al (2020) Availability and quality of surveillance and survey data on HIV prevalence among sex workers, men who have sex with men, people who inject drugs, and transgender women in low- and middle-income countries: review of available data (2001–2017). JMIR Public Health Surveill 6(4):e21688. https://doi.org/10.2196/21688
doi: 10.2196/21688
pubmed: 33200996
pmcid: 7708087
Clifford G, Georges D, Shiels M, Engels E, Albuquerque A, Poynten I et al (2021) A meta-analysis of anal cancer incidence by risk group: toward a unified anal cancer risk scale. Int J Cancer 148(1):38–47. https://doi.org/10.1002/ijc.33185
doi: 10.1002/ijc.33185
pubmed: 32621759
de Vries H, Nori A, Kiellberg Larsen H, Kreuter A, Padovese V, Pallawela S et al (2021) 2021 European Guideline on the management of proctitis, proctocolitis and enteritis caused by sexually transmissible pathogens. J Eur Acad Dermatol Venereol 35(7):1434–43. https://doi.org/10.1111/jdv.17269
doi: 10.1111/jdv.17269
pubmed: 34057249
Nandi A, Nigar T, Das A, Dey YN, dynamics. Plumbago zeylanica (2023) Network pharmacology analysis of to identify the therapeutic targets and molecular mechanisms involved in ameliorating hemorrhoids. 1–15. https://doi.org/10.1080/07391102.2023.2280681
Makris G, Thulasidasan N, Malietzis G, Kontovounisios C, Saibudeen A, Uberoi R et al (2021) Catheter-directed hemorrhoidal dearterialization technique for the management of hemorrhoids: a meta-analysis of the clinical evidence. J Vasc Interv Radiol 32(8):1119–1127. https://doi.org/10.1016/j.jvir.2021.03.548
doi: 10.1016/j.jvir.2021.03.548
pubmed: 33971251
Moore BA, Fleshner PR (2001) Rubber band ligation for hemorrhoidal disease can be safely performed in select HIV-positive patients. Dis Colon Rectum 44(8):1079–1082. https://doi.org/10.1007/bf02234625
doi: 10.1007/bf02234625
pubmed: 11535843
Morandi E, Merlini D, Salvaggio A, Foschi D, Trabucchi EJ (1999) Prospective study of healing time after hemorrhoidectomy: influence of HIV infection, acquired immunodeficiency syndrome, and anal wound infection. Dis Colon Rectum 42(9):1140–4. https://doi.org/10.1007/bf02238565
doi: 10.1007/bf02238565
pubmed: 10496553
Chen B (2019) Molecular mechanism of HIV-1 entry. Trends Microbiol 27(10):878–91. https://doi.org/10.1016/j.tim.2019.06.002
doi: 10.1016/j.tim.2019.06.002
pubmed: 31262533
pmcid: 6744290
Yu F, Jiang SJ; Biology (2022) Small-molecule HIV entry inhibitors targeting gp120 and gp41. 1366:27-43. https://doi.org/10.1007/978-981-16-8702-0_3
Wang P, Yang B, Huang H, Liang P, Long B, Chen L et al (2023) HIV gp120/Tat protein-induced epithelial-mesenchymal transition promotes the progression of cervical lesions. AIDS Res Ther 20(1):82. https://doi.org/10.1186/s12981-023-00577-1
doi: 10.1186/s12981-023-00577-1
pubmed: 37981694
pmcid: 10657494
Wallace DJP (2022) HIV-associated neurotoxicity and cognitive decline: therapeutic implications. Pharmacol Ther 234:108047. https://doi.org/10.1016/j.pharmthera.2021.108047
doi: 10.1016/j.pharmthera.2021.108047
pubmed: 34848202
Schecter A, Berman A, Yi L, Mosoian A, McManus C, Berman J et al (2001) HIV envelope gp120 activates human arterial smooth muscle cells. Proc Natl Acad Sci 98(18):10142–7. https://doi.org/10.1073/pnas.181328798
doi: 10.1073/pnas.181328798
pubmed: 11504923
pmcid: 56929
Liu T, Zhou H, Lu H, Luo C, Wang Q, Peng Y et al (2021) MiR-4729 regulates TIE1 mRNA m6A modification and angiogenesis in hemorrhoids by targeting METTL14. Ann Transl Med 9(3):232. https://doi.org/10.21037/atm-20-3399
doi: 10.21037/atm-20-3399
pubmed: 33708859
pmcid: 7940907
Yu Q, Zhao Y, Zhang X, Li W, Zhang H, Piao S et al (2024) The beneficial effect of Sanhuang ointment and its active constituents on experimental hemorrhoids in rats. J Ethnopharmacol 319:117173. https://doi.org/10.1016/j.jep.2023.117173
doi: 10.1016/j.jep.2023.117173
pubmed: 37741471
Wang C, Lu H, Luo C, Song C, Wang Q, Peng Y et al (2019) miR-412–5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue. Gene 705:167–76. https://doi.org/10.1016/j.gene.2019.04.058
doi: 10.1016/j.gene.2019.04.058
pubmed: 31026569
Eugenin E, Morgello S, Klotman M, Mosoian A, Lento P, Berman J et al (2008) Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. Am J Pathol 172(4):1100–11. https://doi.org/10.2353/ajpath.2008.070457
doi: 10.2353/ajpath.2008.070457
pubmed: 18310503
pmcid: 2276423
Chan M, Aminzai S, Hu T, Taran A, Li S, Kim C et al (2020) A substitution in cGMP-dependent protein kinase 1 associated with aortic disease induces an active conformation in the absence of cGMP. J Biol Chem 295(30):10394–405. https://doi.org/10.1074/jbc.RA119.010984
doi: 10.1074/jbc.RA119.010984
pubmed: 32506052
pmcid: 7383375
Bivalacqua T, Kendirci M, Champion H, Hellstrom W, Andersson K, Hedlund P (2007) Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: influence of in vivo gene therapy of PKG1alpha. BJU Int 99(6):1488–94. https://doi.org/10.1111/j.1464-410X.2007.06794.x
doi: 10.1111/j.1464-410X.2007.06794.x
pubmed: 17355372
Choi S, Park M, Kim J, Park W, Kim S, Lee D et al (2018) TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155–5p-dependent down-regulation of cGMP-dependent kinase 1. J Biol Chem 293(38):14812–22. https://doi.org/10.1074/jbc.RA118.004220
doi: 10.1074/jbc.RA118.004220
pubmed: 30104414
pmcid: 6153283
Di Fulvio M, Lincoln T, Lauf P, Adragna NC (2001) Protein kinase G regulates potassium chloride cotransporter-4 [corrected] expression in primary cultures of rat vascular smooth muscle cells. J Biol Chem 276(24):21046–52. https://doi.org/10.1074/jbc.M100901200
doi: 10.1074/jbc.M100901200
pubmed: 11274213
Xie W, Chen M, Zhai Z, Li H, Song T, Zhu Y et al (2021) HIV-1 exposure promotes PKG1-mediated phosphorylation and degradation of stathmin to increase epithelial barrier permeability. J Biol Chem 296:100644. https://doi.org/10.1016/j.jbc.2021.100644
doi: 10.1016/j.jbc.2021.100644
pubmed: 33839152
pmcid: 8105298
Green L, Yi R, Petrusca D, Wang T, Elghouche A, Gupta S et al (2014) HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3. Am J Physiol-Lung Cell Mol Physiol 306(4):L372-82. https://doi.org/10.1152/ajplung.00193.2013
doi: 10.1152/ajplung.00193.2013
pubmed: 24318111
Hijmans J, Stockleman K, Reiakvam W, Levy M, Brewster L, Bammert T et al (2018) Effects of HIV-1 gp120 and tat on endothelial cell sensescence and senescence-associated microRNAs. Physiol Rep 6(6):e13647. https://doi.org/10.14814/phy2.13647
doi: 10.14814/phy2.13647
pubmed: 29595877
pmcid: 5875545
Deeks S, Tracy R, Douek DC (2013) Systemic effects of inflammation on health during chronic HIV infection. Immunity 39(4):633–645. https://doi.org/10.1016/j.immuni.2013.10.001
doi: 10.1016/j.immuni.2013.10.001
pubmed: 24138880
pmcid: 4012895
Huang W, Tang XX (2021) Virus infection induced pulmonary fibrosis. J Transl Med 19(1):496. https://doi.org/10.1186/s12967-021-03159-9
doi: 10.1186/s12967-021-03159-9
pubmed: 34876129
pmcid: 8649310
Chrysanthidis T, Loli G, Metallidis S, Germanidis G (2017) Mechanisms of accelerated liver fibrosis in HIV-HCV coinfection. AIDS Rev 19(3):148–55
doi: 10.24875/AIDSRev.M17000004
pubmed: 28926561
Teer E, Dominick L, Mukonowenzou N, Essop MF (2022) HIV-related myocardial fibrosis: inflammatory hypothesis and crucial role of immune cells dysregulation. Cells 11(18):2825. https://doi.org/10.3390/cells11182825
doi: 10.3390/cells11182825
pubmed: 36139400
pmcid: 9496784
Guo M, Kook Y, Shannon C, Buch S (2018) Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: implications for HIV-associated PAH. 4:22. https://doi.org/10.1038/s41420-018-0087-9
Schumacher D, Liehn E, Nilcham P, Mayan D, Rattanasopa C, Anand K et al (2021) A neutralizing IL-11 antibody reduces vessel hyperplasia in a mouse carotid artery wire injury model. Sci Rep 11(1):20674. https://doi.org/10.1038/s41598-021-99880-y
doi: 10.1038/s41598-021-99880-y
pubmed: 34667238
pmcid: 8526715
Li G, Chen Y, Greene G, Oparil S, Thompson JA (1999) Estrogen inhibits vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro. Circulation 100(15):1639–1645. https://doi.org/10.1161/01.cir.100.15.1639
doi: 10.1161/01.cir.100.15.1639
pubmed: 10517736
Fedorova O, Shilova V, Zernetkina V, Juhasz O, Wei W, Lakatta E et al (2023) PKG1 silencing of gene mimics effect of aging and sensitizes rat vascular smooth muscle cells to cardiotonic steroids: impact on fibrosis and salt sensitivity. J Am Heart Assoc 12(12):e028768. https://doi.org/10.1161/jaha.122.028768
doi: 10.1161/jaha.122.028768
pubmed: 37301747
pmcid: 10356040
Zhen-Hua L, Yanhong Z, Xue W, Xiao-Fang F, Yuqing Z, Xu L et al (2019) SIRT1 activation attenuates cardiac fibrosis by endothelial-to-mesenchymal transition. 118(0). https://doi.org/10.1016/j.biopha.2019.109227
Zhenlin L, Ekaterina B, Ara P, Rümeyza B, Huguette L, Yuki K et al (2023) Smooth muscle α(v) integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling. Eur Heart J Open 3(2):oead010. https://doi.org/10.1093/ehjopen/oead010
doi: 10.1093/ehjopen/oead010
Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND et al (2018) New insights into TGF-β/Smad signaling in tissue fibrosis. 292(0). https://doi.org/10.1016/j.cbi.2018.07.008
Calamaras TD, Pande S, Baumgartner RAU, Kim SK, McCarthy JC, Martin GL et al (2021) MLK3 mediates impact of PKG1α on cardiac function and controls blood pressure through separate mechanisms. 6(18). https://doi.org/10.1172/jci.insight.149075
Biswas S, Kojonazarov B, Hadzic S, Majer M, Bajraktari G, Novoyatleva T et al (2020) IRAG1 deficient mice develop PKG1β dependent pulmonary hypertension. Cells 9(10):2280. https://doi.org/10.3390/cells9102280
doi: 10.3390/cells9102280
pubmed: 33066124
pmcid: 7601978