p53 upregulated by HIF-1α promotes gastric mucosal epithelial cells apoptosis in portal hypertensive gastropathy



      Portal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of gastrointestinal bleeding. Mucosal apoptosis is an essential pathological feature of PHG. However, whether HIF-1α and p53 are involved in mucosal apoptosis and whether HIF-1α induces PHG by mediating p53 remains unclear.


      Gastric mucosal injury and apoptosis were examined in PHG patients and animal models. The mechanisms of HIF-1α- and p53-mediated apoptosis were analyzed. The GES-1 cell line was used to elucidate the underlying mechanisms using siRNA knockdown of HIF-1α and p53 in a hypoxic environment in vitro.


      Epithelial apoptosis, HIF-1α, and p53 were markedly induced in the gastric mucosa of PHG. Apoptosis was attenuated in mice with HIF-1α- and p53-specific inhibitors. Apoptotic signaling factors were markedly induced in the gastric mucosa of PHG. Inhibition of p53 demonstrably attenuated the mucosal apoptosis; however, it did not affect HIF-1α expression. Conversely, targeted deletion of HIF-1α significantly inhibited p53 expression and attenuated the injury and p53-mediated apoptosis. Bax and Bcl-2 expression can be upregulated and downregulated by p53, respectively, to increasecleaved caspase-3 expression, which can be regulated by HIF-1α.


      These results indicate that HIF-1α regulates the p53-induced mucosal epithelial apoptotic signaling pathway and that HIF-1α and p53 are potential therapeutic targets for PHG.


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        • Tan S.
        • Xu M.
        • Ke B.
        • et al.
        IL-6-driven FasL promotes NF-kappaBp65/PUMA-mediated apoptosis in portal hypertensive gastropathy.
        Cell Death Dis. 2019; 10: 748
        • Rockey D.C.
        An update: portal hypertensive gastropathy and colopathy.
        Clin Liver Dis. 2019; 23: 643-658
        • Smith L.A.
        • Morris A.J.
        • Stanley A.J.
        The use of hemospray in portal hypertensive bleeding; a case series.
        J Hepatol. 2014; 60: 457-460
        • Rajesh S.
        • George T.
        • Philips C.A.
        • et al.
        Transjugular intrahepatic portosystemic shunt in cirrhosis: an exhaustive critical update.
        World J Gastroenterol. 2020; 26: 5561-5596
        • Gines P.
        • Krag A.
        • Abraldes J.G.
        • et al.
        Liver cirrhosis.
        Lancet. 2021; 398: 1359-1376
        • Yi Z.
        • Zhang M.
        • Ma Z.
        • et al.
        Role of the posterior mucosal defense barrier in portal hypertensive gastropathy.
        Biomed Pharmacother. 2021; 144112258
        • Al-Taee A.M.
        • Cubillan M.P.
        • Hinton A.
        • et al.
        Accuracy of virtual chromoendoscopy in differentiating gastric antral vascular ectasia from portal hypertensive gastropathy: a proof of concept study.
        World J Hepatol. 2021; 13: 2168-2178
        • Wang G.L.
        • Semenza G.L.
        Purification and characterization of hypoxia-inducible factor 1.
        J Biol Chem. 1995; 270: 1230-1237
        • Wang X.
        • Wei L.
        • Li Q.
        • Lai Y.
        HIF-1alpha protects osteoblasts from ROS-induced apoptosis.
        Free Radic Res. 2022; : 1-11
        • Moll U.M.
        • Zaika A.
        Nuclear and mitochondrial apoptotic pathways of p53.
        FEBS Lett. 2001; 493: 65-69
        • Madan E.
        • Parker T.M.
        • Pelham C.J.
        • et al.
        HIF-transcribed p53 chaperones HIF-1alpha.
        Nucleic Acids Res. 2019; 47: 10212-10234
        • Wei H.
        • Qu L.
        • Dai S.
        • et al.
        Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis.
        Nat Commun. 2021; 12: 2280
        • Tan S.
        • Wei X.
        • Song M.
        • et al.
        PUMA mediates ER stress-induced apoptosis in portal hypertensive gastropathy.
        Cell Death Dis. 2014; 5: e1128
        • Wu B.
        • Zeng L.
        • Lin Y.
        • et al.
        Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats.
        Cell Res. 2009; 19: 1269-1278
        • Tan S.
        • Li L.
        • Chen T.
        • et al.
        beta-Arrestin-1 protects against endoplasmic reticulum stress/p53-upregulated modulator of apoptosis-mediated apoptosis via repressing p-p65/inducible nitric oxide synthase in portal hypertensive gastropathy.
        Free Radic Biol Med. 2015; 87: 69-83
        • McGrath J.C.
        • Lilley E.
        Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
        Br J Pharmacol. 2015; 172: 3189-3193
        • Tan S.
        • Chen X.
        • Xu M.
        • et al.
        PGE2 /EP4 receptor attenuated mucosal injury via beta-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy.
        Br J Pharmacol. 2017; 174: 848-866
        • Curtis M.J.
        • Bond R.A.
        • Spina D.
        • et al.
        Experimental design and analysis and their reporting: new guidance for publication in BJP.
        Br J Pharmacol. 2015; 172: 3461-3471
        • Kamath P.S.
        • Lacerda M.
        • Ahlquist D.A.
        • et al.
        Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis.
        Gastroenterology. 2000; 118: 905-911
        • Ohta M.
        • Yamaguchi S.
        • Gotoh N.
        • Tomikawa M.
        Pathogenesis of portal hypertensive gastropathy: a clinical and experimental review.
        Surgery. 2002; 131 (Surgery): S165-S170
        • Saikumar P.
        • Dong Z.
        • Patel Y.
        • et al.
        Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury.
        Oncogene. 1998; 17 (Oncogene): 3401-3415
        • Greijer A.E.
        • van der Wall E.
        The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis.
        J Clin Pathol. 2004; 57: 1009-1014
        • Chen D.
        • Li M.
        • Luo J.
        • Gu W.
        Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.
        J Biol Chem. 2003; 278: 13595-13598
        • Gross A.
        • Yin X.M.
        • Wang K.
        • et al.
        Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death.
        J Biol Chem. 1999; 274: 1156-1163
        • Li P.
        • Nijhawan D.
        • Budihardjo I.
        • et al.
        Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.
        Cell. 1997; 91 (Cell): 479-489
        • Nicholson D.W.
        • Thornberry N.A.
        Caspases: killer proteases.
        Trends Biochem Sci. 1997; 22: 299-306
        • Hammond E.M.
        • Giaccia A.J.
        The role of p53 in hypoxia-induced apoptosis.
        Biochem Biophys Res Commun. 2005; 331: 718-725
        • An W.G.
        • Kanekal M.
        • Simon M.C.
        • et al.
        Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha.
        Nature. 1998; 392 (Nature): 405-408
        • Carmeliet P.
        • Dor Y.
        • Herbert J.M.
        • et al.
        Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.
        Nature. 1998; 394 (Nature): 485-490