Therapeutic Reversal of Endothelial Dysfunction in Atherogenesis

DESCRIPTIONprovided by applicantTherapeutic Reversal of Endothelial Dysfunction in Atherogenesis Cardiovascular disease is the leading cause of morbidity and mortality in the worldIn particularatherosclerosis is a life threatening disease strongly associated with risk factors such as elevated cholesterol levelshigh blood pressure and diabetesThere are effective commercially available therapeutics that target these systemic risk factorsYet despite thesethere is still a significant rate of adverse events in patients prescribed these therapeutic and a significant population that suffer adverse cardiovascular events even in the absence of these conventional systemic risk factorsImportantlyin the face of these systemic classical cardiovascular risk factorscertain regions of the arterial vasculature remain relatively resistan to the development of atherosclerotic lesions while some are relatively susceptibleInterestinglythe anatomical locations of these andquot protectedandquotand andquot susceptibleandquotregions are predictable between individuals and even between speciesMultiple lines of evidence suggest that the specific hemodynamic environments within these arterial regions exert a protective influence on the local vascular endotheliumand thus inhibit early lesion developmentIn contrasthemodynamic conditions present in other regions of the vasculature evoke a proinflammatory pro atherogenic dysfunctional state in the endotheliumDespite recent progress in the understanding of some of the biological mechanisms responsible for hemodynamics induced andquot atheroprotectionandquotand andquot atherosusceptibility andquotthese basic discoveries have not yet been translated into therapeutic strategies for the treatment of cardiovascular diseaseDuring the Phase I of our STTR funded projectwe utilized insights regarding the mechanisms underlying endothelial responses to hemodynamic flow to establish a novel cardiovascular drug discovery platformwhich resulted in the identification of novel chemical entities able to mimic hemodynamics induced atheroprotectionIn this Phase II projectwe will continue development of these promising resultsHerethe major goals are todevelop an optimized lead compound from our existing vasoprotective chemical seriescharacterize the mechanism of action of this vasoprotective compoundandevaluate the preclinical efficacy of this optimized lead in an animal model of atherosclerosisThese essential milestones should catalyze this innovative cardiovascular drug discovery effort toward clinical translationthus establishing a new approach to cardiovascular disease therapy PUBLIC HEALTH RELEVANCEAtherosclerosis and its devastating consequencesheart attackstroke and peripheral artery diseaseare the leading causes of death worldwideIn addition to the well known importance of elevated blood pressurecholesterol levels and diabeteschronic inflammation is a potent risk factor that significantly contributes to the progression of atherosclerosisThis project seeks to validate a new approach for the treatment of atherosclerosis by targeting inflammation in the blood vessel wall