METABOLIC DISORDERS (MDS) REPRESENT A HIGH HUMAN AND ECONOMIC COST TO THE SNS AND WHO HAS ESTIMATED THAT BY 2020, ASSOCIATED CARDIOVASCULAR DISEASES WILL BE THE MAIN GLOBAL HEALTH AND SOCIO-ECONOMIC PROBLEM. NUMEROUS EVIDENCE INDICATES THAT A LOW DEGREE OF SYSTEMIC INFLAMMATION USUALLY ACCOMPANIES VARIOUS DMS SUCH AS FAMILIAL HYPERCHOLESTEROLEMIA (FH), OBESITY AND METABOLIC SYNDROME (SM), AND SYSTEMIC INFLAMMATION IS PRIMARILY RESPONSIBLE FOR THE DEVELOPMENT OF PREMATURE ARTERIOSCLEROSIS AND ITS COMPLICATIONS. HOWEVER, THE DIFFERENT MEDIATORS AND IMMUNOLOGICAL MECHANISMS INVOLVED IN THESE DMS ARE BARELY KNOWN. WE HAVE DETECTED AN INCREASE IN EOTAXIN PLASMA LEVELS (CCL11) IN BOTH PATIENTS WITH FH AND APOE-/- MICE UNDERGOING ATEROGENICA DIET AND THE LACK OF THE RECEPTOR OF THIS CHEMOCIN (CCR3) RESULTED IN AN ACCELERATION OF THE ATEROSCLEROTIC PROCESS. THEREFORE, THE FIRST OBJECTIVE WILL ADDRESS THE STUDY OF THE ROLE OF THE CCL11/CCR3 AXIS IN THE SYSTEMIC INFLAMMATION ASSOCIATED WITH HF AND ITS IMMUNOMODULATION BY ORAL LIPID OVERLOAD (SLO). IN ADDITION, THE RENIN-ANGIOTENSIN SYSTEM HAS BEEN INVOLVED IN THE INFLAMMATORY RESPONSE AND ENDOTHELIAL DYSFUNCTION ASSOCIATED WITH MS. THUS, WE HAVE FOUND THAT ANGIOTENSIN-II (ANG-II) INCREASES THE ADHESION OF MONONUCLEAR LEUKOCYTES TO THE ARTERIAL ENDOTHELIUM THROUGH, IN PART, AN INCREASE IN THE EXPRESSION OF CXCL16. SINCE THE MECHANISMS INVOLVED IN THIS RESPONSE AND THE RELEVANCE OF THE CXCL16/CXCR6 AXIS IN PATIENTS WITH MS HAVE NOT BEEN INVESTIGATED, THE SECOND OBJECTIVE WAS TO STUDY THE ROLE OF THE CXCL16/CXCR6 AXIS IN ENDOTHELIAL DYSFUNCTION INDUCED BY ANG-II AND IN SUBJECTS WITH MS. SIMILARLY, THE MECHANISM BY WHICH INCRETINS INHIBIT VASCULAR INFLAMMATION HAS BEEN POORLY ADDRESSED, SINCE MIMETICS OF INCRETINS ARE BEING ADMINISTERED TO PATIENTS WITH TYPE 2 DIABETES (DT2) AND WE HAVE FOUND THAT EXENATIDE REDUCES ARTERIAL ADHESION OF MONONUCLEAR CELLS WHEN INTERACTING WITH THE GLP-1R RECEPTOR, WE ALSO INTEND TO INVESTIGATE THE MECHANISMS INVOLVED IN THE ANTI-INFLAMMATORY ACTIVITY OF EXENATIDE AND ITS IMPACT ON THE INFLAMMATORY STATE OF PATIENTS AND ANIMAL MODELS WITH MS AND DT2D, OBJECTIVE 3. CURRENTLY, PEROXISOME-PROLIFERATION-ACTIVATING RECEPTOR LIGANDS (PPARS) ARE POWERFUL THERAPEUTIC TOOLS IN THE CONTROL OF DIFFERENT DMS. DUAL AGONISTS PPARA/G, ARE MORE POWERFUL CORRECTING THE ALTERATIONS ASSOCIATED WITH MS THAN SELECTIVE PPAR AGONISTS. THEREFORE, AND BASED ON THE DESCRIPTION OF A NEW CLASS OF DUAL AGONISTS PPARA/G BIOACTIVE WITH BENZOPIRANICA STRUCTURE BY OUR GROUP, WE WILL ALSO SYNTHESISE NEW DUAL AGONISTS PPARA/G OR PAN PPAR WITH THIS STRUCTURE AND EVALUATE THEIR PHARMACOLOGICAL ACTIVITY IN RELEVANT IN VITRO AND IN VIVO MODELS OF ENDOTHELIAL DYSFUNCTION, INFLAMMATION AND DM, OBJECTIVE 4. IN ORDER TO MEET THESE CHALLENGES, A MULTIDISCIPLINARY TEAM (BASIC BIOMEDICAL RESEARCHERS AND CLINICS AS WELL AS CHEMICALS) HAS BEEN UNITED SO THAT THEIR JOINT EFFORT ALLOWS A) TO ELUCIDATE NEW IMMUNOLOGICAL AGENTS AND MECHANISMS INVOLVED IN SYSTEMIC INFLAMMATION ASSOCIATED WITH DIFFERENT DM, B) TO DETECT NEW BIOMARKERS OF CARDIOVASCULAR RISK AND C) TO GENERATE NOVEL PHARMACOS WITH THERAPEUTIC POTENTIAL IN THE CONTROL OF METABOLIC INFLAMMATION. OUR FINAL INTEREST IS TO CARRY OUT A PROPER TRANSLATIONAL RESEARCH FOR A RAPID APPLICATION OF OUR FINDINGS TO THE CLINIC.
