MULTI-TARGET DIRECTED LIGANDS (MTDLS) WITH ANTI-INFLAMMATORY ACTIVITY IMPROVE LIPID-INDUCED ENDOTHELIAL DYSFUNCTION

Abstract

Introduction The World Health Organization estimates that Cardiovascular diseases (CVDs) are responsible for 17.9 million lives per year. Inflammation plays a major role in the pathology of atherosclerosis, a major component of CVDs. Of special interest, metabolic disorders, like obesity, insulin resistance, type 2 diabetes, are associated with a chronic state of low-grade inflammation predisposing to CVDs. Lipid disorders in these conditions trigger an immunoinflammatory response in medium-sized and large arteries predisposing to atherosclerosis. Evidence show that endothelial dysfunction (ED) is one of the early events in the pathogenesis of atherosclerotic progression. Previous studies show that the Free fatty acids (FFAs) are major risk factors of CVDs and are closely related to metabolic syndrome (MetS). Recent observation implicated FFAs in inducing vascular inflammation via a number of intertwining pathways possibly leading to ED. Hypothesis Vascular exposure to high FFA levels will induce ED through the activation of multiple inflammatory pathways. Simultaneous interruption of these pathways using multi-target directed ligands (MTDLs) will improve endothelial function. Results ED was studied in rat thoracic aortic tings resulting from ex vivo exposure to increased concentrations of saturated fatty acids (800 M palmitic acid). Only treatment with anti-inflammatory triple targeting MTDLs affecting cyclooxygenase, lipoxygenase, and PPAR restored endothelium-dependent relaxation. Whereas the impact of the triple targeting MTDL appeared to be similar to the single targeting pioglitazone in acute ex vivo exposure, it was more effective on aortic tissues isolated from prediabetic rats with chronic vascular inflammation. Importantly, treatment with the triple targeting MTDL restored inward rectifier potassium channel expression in tissues exposed to palmitic acid. Conclusions Ex vivo pretreatment with MTDLs will prevent the inflammatory response and reverse the functional Impairment.