Protective role of PI3‐kinase‐Akt‐eNOS signalling pathway in intestinal injury associated with splanchnic artery occlusion shock

• Published in: British journal of pharmacology Vol. 151; no. 3; pp. 377 - 383
• Main Authors: Roviezzo, F, Cuzzocrea, S, Di Lorenzo, A, Brancaleone, V, Mazzon, E, Di Paola, R, Bucci, M, Cirino, G
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2007; Nature Publishing; Nature Publishing Group
• Subjects: adhesion proteins; Akt; Animals; Arterial Occlusive Diseases - physiopathology; Benzoquinones - pharmacology; Biological and medical sciences; Blotting, Western; Cardiology. Vascular system; Cell Adhesion Molecules - metabolism; Chromones - pharmacology; Dose-Response Relationship, Drug; eNOS; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Ileum - drug effects; Ileum - metabolism; Ileum - pathology; Intestines - blood supply; Intestines - injuries; Intestines - physiopathology; ischemia‐reperfusion; Lactams, Macrocyclic - pharmacology; Male; Medical sciences; Mice; Morpholines - pharmacology; Neutrophils - drug effects; Neutrophils - pathology; Nitric Oxide Synthase Type III - metabolism; Peroxidase - metabolism; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation - drug effects; PI3K; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Reperfusion Injury - physiopathology; Research Papers; Signal Transduction - drug effects; Signal Transduction - physiology; splanchnic artery occlusion; Splanchnic Circulation - physiology; Shock; eNOS; Digestive system; Enzyme; Transferases; Ischemia reperfusion; Gut; Akt protein kinase; Akt; ischemia-reperfusion; Adhesion; Protein; Prevention; Signal transduction; splanchnic artery occlusion; PI3K; Kinase; Lesion; Artery occlusion; adhesion proteins
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707233

Background and purpose: Endothelial NO synthase (eNOS) is a dynamic enzyme tightly controlled by co‐ and post‐translational lipid modifications, phosphorylation and regulated by protein‐protein interactions. Here we have pharmacologically modulated the activation of eNOS, at different post‐translational levels, to assess the role of eNOS‐derived NO and of these regulatory mechanisms in intestinal injury associated with splanchnic artery occlusion (SAO) shock. Experimental approach: SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk for 45 min followed by 30 min of reperfusion. During ischemia, 15 min prior to reperfusion, mice were given geldanamycin, an inhibitor of hsp90 recruitment to eNOS, or LY‐294002 an inhibitor of phosphatidylinositol 3‐kinase (PI3K), an enzyme that initiates Akt–catalysed phosphorylation of eNOS on Ser1179. After 30 min of reperfusion, samples of ileum were taken for histological examination or for biochemical studies. Key results: Either LY‐294002 or geldanamycin reversed the increased activation of eNOS and Akt observed following SAO shock. These molecular effects were mirrored in vivo by an exacerbation of the intestinal damage. Histological damage also correlated with neutrophil infiltration, assessed as myeloperoxidase activity, and with an increased expression of the adhesion proteins: ICAM‐I, VCAM, P‐selectin and E‐selectin. Conclusions and implications: Overall these results suggest that activation of the Akt pathway in ischemic regions of reperfused ileum is a protective event, triggered in order to protect the intestinal tissue from damage induced by ischaemia/reperfusion through a fine tuning of the endothelial NO pathway. British Journal of Pharmacology (2007) 151, 377–383; doi:10.1038/sj.bjp.0707233