Targeting vascular inflammation and the adaptive immune response is emerging as novel strategy beyond lipid lowering therapies to reduce the burden of atherosclerosis, the primary cause of mortality from cardiovascular diseases in the United States. The clinical detection and quantitation of nitric oxide-dependent fatty acid nitration products (nitroalkenes) among other fatty acids species, has sparked the interest on novel anti-inflammatory lipids targeting the immune system. Recent improvements in the methodology of detection and advances in metabolomics and lipidomics strategies have more precisely determined the abundance of the fatty acid nitration milieu. These novel tools have identified conjugated linoleic acid (CLA) as the preferential substrate for fatty acid nitration in humans. Most importantly, it has been determined that CLA nitration is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2). However, whether parenteral nitro-CLA formation has functional benefits and salutary properties in the cardiovascular system remains to be explored. Herein, it is shown that nitro-CLA formation readily translates into anti-inflammatory mechanisms in the vasculature. In an experimental model of high-fat diet induced vascular inflammation, formation of nitro-CLA efficiently reduces arterial stiffness, a hallmark of obesity-induced vascular damage. Nitro-CLA reduces macrophage chemotaxis and adhesion to the endothelium in vivo, thus suggesting a critical role of CLA nitration in the prevention of vascular inflammatory responses. In addition, CLA nitration significantly reduces obesity-induced activation of inflammatory cells and promotes a robust anti-inflammatory phenotype switch favoring macrophage polarization towards M2 (alternative) versus M1 (classical) activation. Finally, nitro-CLA serves as an agonist of the PPAR? nuclear receptor, a key transcription factor involved in the regulation of macrophage polarization. Based on this evidence, this proposed project will test the central hypothesis that enhancing the endogenous production of nitro-conjugated linoleic acid promotes macrophage polarization towards an anti-inflammatory phenotype and protects against atherosclerosis. To address this hypothesis the following Specific Aims are proposed.
Aim 1 : Determine the role of nitro-CLA in macrophage anti-inflammatory properties promoting an M1 to M2 polarization.
Aim 2 : Define PPAR? as a key transcription factor mediating nitro-CLA anti-inflammatory mechanisms in macrophages.
Aim 3 : Determine that nitro-CLA-mediated macrophage PPAR? activation inhibits atherosclerosis. It is expected that with this proposal we will better define the anti-inflammatory properties of CLA nitration and establish their oral bioavailability as a novel therapeutic strategy against atherosclerosis.
Despite significant clinical advances in lipid-lowering therapies, atherosclerosis continues to be the primary underlying culprit in mortality rates from cardiovascular diseases. The proposed project is relevant for the public health because it will establish a novel pharmacological approach to target vascular inflammation using orally bioavailable nitrated conjugated linoleic acid against atherosclerosis.
