METABOLIC DISORDERS (MD) CONTRIBUTE TO A DISPROPORTIONATE BURDEN OF ILLNESS AND ECONOMIC COST TO THE NATIONAL HEALTH SYSTEM AND THE WHO HAS ESTIMATED THAT BY 2020 THE ASSOCIATED CARDIOVASCULAR DISEASES (CVD) WILL BE THE MAIN SANITARY AND SOCIO-ECONOMIC PROBLEM WORLD WIDE. A LOW-GRADE SYSTEMIC INFLAMMATION IS ASSOCIATED WITH FAMILIAL HYPERCHOLESTEROLEMIA (FH) WHICH SEEMS TO BE THE MAIN DRIVER OF PREMATURE ATHEROSCLEROSIS. IN ADDITION, ABDOMINAL AORTIC ANEURYSM (AAA), A LOCALIZED DILATATION OF THE ABDOMINAL AORTA, OCCURS IN UP TO 9% ADULTS OVER 65 YEARS. PATHOLOGICAL FEATURES OF AAA INCLUDE CHRONIC VASCULAR INFLAMMATION OF THE AORTIC WALL AND INCREASED NEOVASCULARIZATION. NOWADAYS, THE ONLY CLINICAL THERAPEUTIC APPROACH TO AAA IS THE SURGICAL REPAIR AND IT IS IMPORTANT TO FIND PHARMACOLOGICAL TOOLS TO HALT ITS PROGRESSION. NOTABLY, THE DIFFERENT IMMUNE PLAYERS AND MECHANISM IMPLICATED IN THESE DISEASES REMAINS LARGELY UNKNOWN. WE FOUND THAT PLASMA LEVELS OF CCL11 ARE ELEVATED IN PATIENTS WITH FH AND IN APOE-/- MICE SUBJECTED TO AN ATHEROGENIC DIET. DELETION OF CCL11 RECEPTOR (CCR3) ACCELERATES ATHEROSCLEROSIS IN THESE ANIMALS, SUGGESTING THAT CCL11/CCR3 AXIS MAY EXERT PROTECTIVE EFFECTS. ADMINISTRATION OF AN ORAL FAT LOAD (OFL) WITH A COMMERCIAL PREPARATION OF LONG CHAIN TRIGLYCERIDES (OMEGA6/OMEGA3 RATIO IS > 20/1) TO FH PATIENTS SEEMS TO CAUSE ACUTE CHANGES IN THIS AXIS. THUS, IN OBJECTIVE 1 WE WILL STUDY THE IMMUNOMODULATORY EFFECTS OF THE ACUTE (HUMANS) AND CHRONIC (MICE) ADMINISTRATION OF THIS NUTRACEUTICAL IN THE SYSTEMIC INFLAMMATION ASSOCIATED TO FH. ADDITIONALLY, CCL1 WAS ALSO DETECTED IN HUMAN PLASMA AND WITHIN AAA LESION. MOREOVER, OUR PRELIMINARY STUDIES HAVE REVEALED INCREASED INFILTRATION OF CCR3+ CELLS IN THE AAA LESION OF APOE-/- MICE AND PLASMA LEVELS OF CCL11. THEREFORE, IN OBJECTIVE 2 WE WILL STUDY THE ROLE OF CCL11/CCR3 AXIS AND EOSINOPHILIC INFLAMMATION IN AAA FORMATION TO PROVIDE NEW INSIGHTS IN THE IMMUNE MECHANISM INVOLVED IN THIS CLINICAL ENTITY AND FIND NOVEL THERAPEUTIC APPROACHES. LIKEWISE, LITTLE IS KNOWN REGARDING THE MECHANISMS OF ACTION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS IN THE MODULATION OF VASCULAR INFLAMMATION. IN OBJECTIVE 3 WE WILL INVESTIGATE THE MECHANISMS INVOLVED IN THE ANTI-INFLAMMATORY ACTIVITY OF THESE NEW DRUGS AND THEIR IMPACT ON ENDOTHELIAL DYSFUNCTION AND SYSTEMIC INFLAMMATION IN PATIENTS WITH FH AT HIGH-INTENSITY STATIN TREATMENT. FINALLY, LIVER X RECEPTORS (LXRS) LIGANDS HAVE EMERGED AS NEW THERAPEUTIC TOOLS IN THE CONTROL OF INFLAMMATORY DISORDERS SUCH AS ATHEROSCLEROSIS. HOWEVER, ITS ACTIVATION CAN DISPLAY ADVERSE EFFECTS SUCH AS HYPERTRIGLYCERIDEMIA BUT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-A (PPARA) ACTIVATION MIGHT COUNTERACT THIS ACTION. THUS, IN OBJECTIVE 4 WE WILL SYNTHESIZE NEW BENZOPYRANS DERIVATIVES (LEADS) WITH DUAL LXRB/PPARA ACTIVITY AND EVALUATE THEIR ACTIVITY IN ENDOTHELIAL DYSFUNCTION, INFLAMMATION AND METABOLIC DERANGEMENTS. FOR THESE PURPOSES, A MULTIDISCIPLINARY TEAM (BASIC AND CLINICAL BIOMEDICAL RESEARCHERS AND CHEMISTS) HAVE JOINED THEIR EFFORTS TO A) ELUCIDATE NOVEL IMMUNE PLAYERS AND MECHANISMS INVOLVED IN THE SYSTEMIC INFLAMMATION ASSOCIATED TO DIFFERENT MD, B) DETECT NEW CARDIOVASCULAR RISK BIOMARKERS AND C) GENERATE NEW THERAPIES WITH POTENTIAL APPLICATION IN THE CONTROL OF THE METABOLIC INFLAMMATION. OUR FINAL AIM IS TO PROVIDE THE BASIS FOR A PROPER TRANSLATIONAL RESEARCH AND, A RAPID APPLICATION TO THE CLINIC.
