Cell signalling of the epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) axis in HIV associated pre-eclampsia.

Abstract

Background: Epidermal growth factor is a protein which, when bound to epidermal growth factor receptor, facilitates cell proliferation and differentiation, hence is vital for a successful normal pregnancy. In preeclampsia (PE), EGFR signalling is dysregulated leading to decline in blood flow to the fetus. Furthermore, aberrant EGF/EGFR signalling leads to deficient trophoblast development. The Trans-Activator of transcription (Tat) protein, displayed in HIV inhibits EGF related processes. Since PE and HIV infection are the leading causes of both maternal morbidity and mortality in South Africa; this study focuses on examining EGF/EGFR signalling in HIV associated PE and their effect on downstream targets. Methods: Post ethics approval; this study selected 80 pregnant women from an archive of retrospectively stored serum samples. The samples were stratified by type of pregnancy and HIV status into the following groups: a) HIV negative preeclamptic women (n=20), b) HIV positive preeclamptic women (n=20), c) HIV negative normotensive pregnant women (n=20) and d) HIV positive normotensive pregnant women (n=20). Both EGF and EGFR were multiplexed in a Bioplex immunoassay technique to determine their serum concentration across study groups at term. Results: Based on the clinical data, statistically significant differences were obtained across groups for gestational age (p < 0.001), birth weight (p < 0.001), systolic BP (p < 0.001), BMI (p = 0.048), diastolic BP (p < 0.001) and maternal weight (p = 0.002). However, no statistical significance was observed for maternal age across all study groups (p = 0.065). A significant decline in EGF levels were observed in PE compared to normotensive pregnancy, regardless of HIV status (p = 0.0214). Based on HIV status, no statistical significance in EGF concentration was observed (p = 0.6593). EGFR was significantly elevated in normotensive pregnant compared to preeclamptic women (p < 0.0001) (Figure 2A). In contrast, there were no significant differences of EGFR based on HIV status alone (p = 0.2092) (Figure 2B). However, a significant up-regulation of EGFR was observed between normotensive HIV positive compared to PE HIV positive women. Normotensive HIV negative was also significantly up-regulated compared to PE HIV positive (p < 0.0001). Normotensive HIV positive was significantly higher than PE HIV negative. Also, of note within the PE group, HIV negative EGFR levels were significantly up-regulated compared to the HIV positive group. Conclusion: This novel study outlines a significant down-regulation of EGF and EGFR in PE compared to normotensive pregnant women; regardless of HIV status. No significant differences were observed based on HIV status alone for serum EGF levels. This could be due to immune reconstruction as all HIV infected patients received HAART, hence may have neutralised EGF levels. Furthermore, these findings may be attributed to the Trans-Activator of transcription (Tat) protein which prevents EGF related function. However, for serum EGFR concentration there were significant differences within PE group based on HIV status. Significant differences were observed between normotensive and preeclamptic based on HIV status, except for normotensive HIV negative vs PE HIV negative. Furthermore, there was no significance in the normotensive group based on HIV status. The decreased levels of serum EGF/ EGFR could possibly be used as a biomarker for PE development during pregnancy.

Isendlalelo: I-Epidermal growth factor iyiphrotheni okuthi uma ihlangene ne-epidermal growth factor receptor, isiza ngokwandisa amaseli nokuwehlukanisa, yingakho ibalulekile ekukhulelweni okujwayelekile okuphumelelayo. Ku-preeclampsia (PE), ukusayinda kwe-EGFR kuyaphazamiseka okuholela ekwehleni kokugeleza kwegazi ku-fetus. Ngaphezu kwalokho, ukusayina kwe-EGF / EGFR ngendlela eyehlukile kunalena eyejwayelekile kuholela ekushodeni kwe-trophoblast. I-Trans-Activator of transcription (Tat) protein ivimbela izinqubo ezihlobene ne-EGF uma ihlangene neHIV. Njengoba izifo ze-PE kanye ne-HIV kuyizimbangela ezihamba phambili zokugula nokufa komama eNingizimu Afrika; lolu cwaningo lugxile ekuhloleni ukusayina kwe-EGF / EGF-R ku-PE ehlobene ne-HIV kanye nomphumela wazo uma zixhuma endaweni eziyihlosile maphansi neseli. Izindlela: Ngemva kokugunyazwa kokuziphatha; lolu cwaningo lukhethe abesifazane abakhulelwe abangama-80 kungobo yomlando yamasampula e-serum agcinwe ngokudlule. Amasampula ahlukaniswa ngohlobo lokukhulelwa kanye nesimo se-HIV emaqenjini alandelayo: a) abesifazane abakhulelwe abangenayo i-HIV kodwa abanomfutho wegazi ophakeme (n=20), b) abesifazane abakhulelwe abane-HIV nomfutho wegazi ophakeme (n=20), c) abesifazane abakhulelwe abangenayo i-HIV futhi abanomfutho wegazi ojwayelekile (n=20), kanye d) nabesifazane abakhulelwe abane-HIV kodwa banomfutho wegazi ojwayelekile (n=20). Kokubili i-EGF ne-EGF-R zacwaningwa ngendlela ye-Bioplex immunoassay ukuze kutholwe inani lweserum yazo kuwo wonke amaqembu ocwaningo ngesikhathi. Imiphumela: Ngokubuka idatha esungulwe yimtholampilo, umehluko obalulekile ngokwezibalo watholwa kuwo wonke amaqembu eminyaka yobudala (p <0.001), isisindo sokuzalwa (p <0.001), i-systolic BP (p <0.001), BMI (p = 0.048), i-diastolic BP (p <0.001) kanye nesisindo sikamama (p = 0.002). Kodwa-ke awukho umehluko omkhulu ngokwezibalo owabonwa ngeminyaka yobudala bomama kuwo wonke amaqembu ocwaningo (p = 0.065). Ukwehla ngokwezibalo okubalulekile kwe-EGF kwabonwa i-PE uma kuqhathaniswa nokukhulelwa kwe-normotensive, kungakhathaliseki isimo se-HIV (p = 0.0214). Ngokubuka isimo se-HIV, akukho ukubaluleka kwezibalo kwe-EGF okuphawulwe (p = 0.6593). Kungakhathalekile ukuthi ngabe i-HIV ithini, i-EGFR iphakanyiswe kakhulu kumanormotensive abakhulelwe ngokuqhathaniswa nabesifazanebe-preeclamptic (p < 0.0001). Ngokuphambene, kwakungekho umehluko ophawulekayo we-EGFR ngokusekelwe esimweni se-HIV (p = 0.2092). Kodwa-ke, ukulawulwa okubalulekile kwe-EGFR kwabonwa phakathi kwe-HIV positive normotensive uma kuqhathaniswa nabesifazane abakhulelwe abangenayo ixvi HIV (p = 0.001); ngaleyo nkathi ukwehla okubalulekile kwe-EGFR kwaboniswe kuwo wonke amaqembu ocwaningo (p = 0.001). Isiphetho: Lolu cwaningo lwenoveli luveza ukwehla okubalulekile kwe-EGF ne-EGFR ku-PE uma kuqhathaniswa nabesifazane abakhulelwe abajwayelekile; kungakhathaliseki isimo se-HIV. Awukho mehluko omkhulu obonwe ngokusekelwe esimweni se-HIV. Lokhu kungase kube ngenxa yokwakhiwa kabusha kwamasosha omzimba njengoba zonke iziguli ezine-HIV zithole i-HAART, yingakho kungase kulinganise amazinga e-EGF/EGFR. Ngaphezu kwalokho, lokhu okutholakele kungase kubalulwe ku-Trans-Activator of transcription (Tat) protein evimbela umsebenzi ohlobene ne-EGF. I-down-regulation ye-EGF/EGFR ingase isetshenziswe njengokuhlola inkomba yokubikezela ukuthuthukiswa kwe-PE ngesikhathi sokukhulelwa.