Thursday, 21st June 2018
Cell Biology and Immunology
               Prostanoids actions in inflammatory processes








Miguel Ángel Íñiguez Peña







Research summary:

Lipid mediators as prostanoids and cholesterol derivatives play an essential role in inflammatory processes associated to the onset and development of a number of pathologies as cardiovascular diseases. Prostanoids participate in the inflammatory response and exert important actions in the cardiovascular system, modulating vascular homeostasis and participating in the pathogenesis of vascular diseases. Their importance in inflammation and in maintaining cardiovascular homeostasis is highlighted by clinical experience with drugs inhibiting their production as NSAIDs. In spite of their well-known properties as anti-inflammatory drugs, recent studies have shown that cyclooxygenase-2 selective NSAIDs inhibitors increase the risk of adverse cardiovascular side effects. On the other hand, oxysterols and drugs acting as LXR ligands play a central regulatory role in lipid uptake, metabolism and efflux through their properties as transcriptional regulators of gene expression. In addition to their function in lipid metabolism, LXRs have also been found to modulate the immune response and inflammation. These properties have made them particularly attractive targets for intervention in human cardiovascular diseases.



Hypertrophic effect of FP receptor agonists in rat neonatal cardiomyocytes. Cardiomyocytes were treated with prostaglandin (PG) F2α or Fluprostenol (1 μM)and visualized with an antibody antiα-sarcomeric actin revealed with a secondary antibody coupled to Alexa 488 (green). The cell area analysis showed an increase in cell size in the treated cells compared to control.





Abdominal aortic aneurysm (AAA) formation in apoE-/- mice infused with Angiotensin II (AngII) or saline as a control. Staining of cross sections taken from the suprarenal region of the aorta shows dilatation and thickening of the abdominal aortic wall and alteration of the elastic laminain mice treated with AngII.



Based on these observations and our previous studies, the main objectives of our line of research include:analysis of the effects of prostanoids and LXR ligands in different cell types as leukocytes and cardiomyocytes, among others; study of the signal transduction pathways mediating hypertrophic effects of prostanoids on cardiomyocytes; and investigation of the contribution of prostanoid –mediated events and LXR ligands to the progression of abdominal aortic aneurysm, by the use of cellular models and an experimental model of this disease in Apo-E null mice and Cox-2 null mice.
Research on the molecular and cellular basis of the actions of prostanoids and LXRs in the cardiovascular pathophysiology is required to clearly understand the benefits and risks of pharmaceutical intervention with COX inhibitors as NSAIDs or synthetic LXR ligands on cardiovascular diseases.


Relevant publications:

  • Díaz-Muñoz MD, Osma-García IC, Iñiguez MA, Fresno M. Cyclooxygenase-2 deficiency in macrophages leads to defective p110γ PI3K signaling and impairs cell adhesion and migration. J Immunol. 2013 Jul 1;191(1):395-406. PubMed PMID: 23733875.
  • Díaz-Muñoz MD, Osma-García IC, Fresno M, Iñiguez MA. Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem J. 2012 Apr 15;443(2):451-61. PubMed PMID: 22268508.
  • Díaz-Muñoz MD, Osma-García IC, Cacheiro-Llaguno C, Fresno M, Iñiguez MA.Coordinated up-regulation of cyclooxygenase-2 and microsomal prostaglandin Esynthase 1 transcription by nuclear factor kappa B and early growth response-1 in macrophages. Cell Signal. 2010 Oct;22(10):1427-36. PubMed PMID: 20546888.
  • Grau R, Punzón C, Fresno M, Iñiguez MA. Peroxisome-proliferator-activatedreceptor alpha agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1. Biochem J. 2006 Apr 1;395(1):81-8. PubMed PMID: 16343055
  • Duque J, Fresno M, Iñiguez MA. Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem. 2005 Mar 11;280(10):8686-93. PubMed PMID: 15632146.