GHRP-6 azapeptide analogs MPE-001 and MPE-003 reduce and regress atherosclerotic lesions in mice.

Atherosclerosis involves the accumulation of modified lipoproteins in macrophages within artery walls, a process driven by the scavenger receptor CD36 (cluster of differentiation-36). This uptake leads to foam cell formation and the progression of atherosclerotic plaques, which can cause heart attacks and strokes. The role of CD36 makes it a compelling therapeutic target for preventing or reversing this disease. This research explores novel azapeptide analogs of Growth Hormone-Releasing Peptide-6 (GHRP-6), specifically designed to act as selective CD36 ligands, to assess their potential to combat atherosclerosis by modulating macrophage activity and inflammation.

Male apoe-/- mice were fed a high-fat high-cholesterol (HFHC) diet from age 4 to 19 weeks to induce atherosclerosis. In a regression study, mice were then switched to normal chow and treated daily for 9 weeks with 300 nmol/kg of MPE-001 ([aza-Tyr4]-GHRP-6) or MPE-003 ([aza-(N,N-diallylaminobut-2-ynyl)Gly4]-GHRP-6). In a progression study, mice were kept on the HFHC diet throughout and treated with the same compounds. Lesion area in the aortic arch and sinus was the primary endpoint. A control group of apoe-/-cd36-/- mice was used to confirm CD36 dependency.

Both azapeptides demonstrated significant anti-atherosclerotic effects. In the regression study (mice switched to chow), treatment with MPE-001 or MPE-003 decreased lesion progression in the aortic arch and actively reduced aortic sinus lesion areas to levels below those measured before treatment began. In the progression study (mice on continuous HFHC diet), the azapeptides also reduced lesion progression in the aortic vessel and sinus. This atheroprotective effect was linked to a shift in macrophage polarization within the lesions, indicated by a reduced ratio of iNOS+ to CD206+ macrophages, suggesting a more anti-inflammatory M2-like phenotype.

Azapeptides decreased lesion progression in the aortic arch and reduced aortic sinus lesion areas below pre-existing lesions levels in apoe-/- mice which were switched to chow diet. Additionally, treated mice exhibited lower plasma levels of inflammatory cytokines. Monocytes from these mice showed altered mitochondrial oxygen consumption rates, consistent with an M2-like phenotype. Crucially, these beneficial effects were not observed in apoe-/-cd36-/- mice, confirming the mechanism is dependent on the CD36 receptor.