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Human esophageal microvascular endothelial cells respond to acidic pH stress by PI3K/AKT and p38 MAPK-regulated induction of Hsp70 and Hsp27. Am J Physiol Cell Physiol 2006 Nov;291(5):C931-45



Pubmed ID




Scopus ID

2-s2.0-33751097760   65 Citations


The heat shock response maintains cellular homeostasis following sublethal injury. Heat shock proteins (Hsps) are induced by thermal, oxyradical, and inflammatory stress, and they chaperone denatured intracellular proteins. Hsps also chaperone signal transduction proteins, modulating signaling cascades during repeated stress. Gastroesophageal reflux disease (GERD) affects 7% of the US population, and it is linked to prolonged esophageal acid exposure. GERD is characterized by enhanced and selective leukocyte recruitment from esophageal microvasculature, implying activation of microvascular endothelium. We investigated whether phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK regulate Hsp induction in primary cultures of human esophageal microvascular endothelial cells (HEMEC) in response to acid exposure (pH 4.5). Inhibitors of signaling pathways were used to define the contribution of PI3K/Akt and MAPKs in the heat shock response and following acid exposure. Acid significantly enhanced phosphorylation of Akt and MAPKs in HEMEC as well as inducing Hsp27 and Hsp70. The PI3K inhibitor LY-294002, and Akt small interfering RNA inhibited Akt activation and Hsp70 expression in HEMEC. The p38 MAPK inhibitor (SB-203580) and p38 MAPK siRNA blocked Hsp27 and Hsp70 mRNA induction, suggesting a role for MAPKs in the HEMEC heat shock response. Thus acidic pH exposure protects HEMEC through induction of Hsps and activation of MAPK and PI3 kinase pathway. Acidic exposure increased HEMEC expression of VCAM-1 protein, but not ICAM-1, which may contribute to selective leukocyte (i.e., eosinophil) recruitment in esophagitis. Activation of esophageal endothelial cells exposed to acidic refluxate may contribute to GERD in the setting of a disturbed mucosal squamous epithelial barrier (i.e., erosive esophagitis, peptic ulceration).

Author List

Rafiee P, Theriot ME, Nelson VM, Heidemann J, Kanaa Y, Horowitz SA, Rogaczewski A, Johnson CP, Ali I, Shaker R, Binion DG


Christopher P. Johnson MD Professor in the Surgery department at Medical College of Wisconsin
Reza Shaker MD Assoc Provost, Sr Assoc Dean, Ctr Dir, Chief, Prof in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Adhesion Molecules
Cell Survival
Class I Phosphatidylinositol 3-Kinases
DNA-Binding Proteins
Electrophoresis, Gel, Two-Dimensional
Endothelial Cells
Gene Expression Regulation
HSC70 Heat-Shock Proteins
HSP110 Heat-Shock Proteins
HSP27 Heat-Shock Proteins
Heat Shock Transcription Factors
Heat-Shock Proteins
Hydrogen-Ion Concentration
Neoplasm Proteins
Phosphatidylinositol 3-Kinases
Protein Transport
Proto-Oncogene Proteins c-akt
RNA, Messenger
RNA, Small Interfering
Signal Transduction
Transcription Factors
p38 Mitogen-Activated Protein Kinases
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00