Title : The anti-atherosclerotic agent MPE-298 mediates mitochondrial oxidative stress through trafficking of the cluster of differentiation 36 (CD36) receptor in macrophages
Abstract:
It is known that oxidized low density lipoproteins (oxLDL) interaction with the cluster of differentiation 36 (CD36)/SR-B2, a scavenger membrane protein, at the surface of macrophages, leads to an internalization of oxLDL in the cells. During atherosclerosis development, an excessive internalization of oxLDL by CD36 in the macrophages leads to the formation of foam cells, which induces mitochondrial oxidative stress, inflammation, and plaque formation. The cyclic azapeptide MPE-298 is a synthetic molecule derived from the growth hormone releasing peptide-6 (GHRP-6) and has been found to selectively bind to CD36 with high affinity. Featuring anti-inflammatory and anti-atherosclerotic activities in apolipoprotein-E deficient mice as a model for atherosclerosis, the azapeptide induced a significant reduction of aortic lesions progression, plaque instability biomarkers and release of pro-inflammatory cytokines. To characterize the mechanism of action of MPE-298, in vitro studies were conducted in macrophages, with results showing the peptide’s modulatory effect on the development of atherosclerosis and inflammation. The mitochondrial oxidative stress induced by oxLDL was found reduced after macrophage incubation with MPE-298, in a CD36-dependent manner. MPE-298 was found to induce CD36 internalization and its intracellular trafficking via the endosomal pathway towards lysosomes as assessed by fluorescence microscopy. Although MPE-298 was found to induce CD36 internalization in the same manner as oxLDL, CD36, after binding to oxLDL, was rather directed towards the early endosomes. The distinctive intracellular trafficking and disposition of CD36 after its binding to the MPE-298 azapeptide, as compared to after its binding to oxLDL, might result in the differential effect on mitochondrial oxidative stress that was observed in macrophages, highlighting the dampening effect of MPE-298 on inflammation.
Audience Take Away
- Atherosclerosis is the primary cause of heart disease and stroke. Our studies introduce a novel peptide and therapeutic target, as well as their mechanisms, to potentially help prevent or treat atherosclerosis, especially in patients who do not respond well to current treatments available, such as statins or ezetimibe. This is an important unmet need in patients, which our research can help fulfill.
- The presentation will cover our methodologies, from our in vitro studies using various cell culture techniques to in vivo studies using an atherosclerotic model of mice. This might help give insight to researchers in the audience potentially interested in studying certain subjects requiring the same techniques.
- The receptor we will focus on during the presentation, the CD36 receptor, is a receptor expressed in a ubiquitous way in various cell types and represents an important therapeutic target in a variety of pathologies, not just atherosclerosis. Our presentation might help researchers in the audience in various domains of expertise gain interest in CD36 as a therapeutic target and expand their studies.
