Atheroprotective and atheroregressive potential of azapeptide derivatives of GHRP-6 as selective CD36 ligands in apolipoprotein E-deficient mice.

Background And Aims: Scavenger receptor class B member 3, also known as cluster of differentiation-36 (CD36) receptor, is involved in the uptake and accumulation of modified lipoprotein in macrophages, driving atherosclerosis progression. Azapeptide analogs of growth hormone-releasing peptide-6 (GHRP-6) have been developed as selective CD36 ligands and evaluated for their anti-atherosclerotic properties in apoe mice.

Methods: From 4 to 19 weeks of age, male apoe mice were fed a high fat high cholesterol (HFHC) diet, then switched to normal chow and treated daily with 300 nmol/kg of MPE-001 ([aza-Tyr]-GHRP-6) or MPE-003 ([aza-(N,N-diallylaminobut-2-ynyl)Gly]-GHRP-6) for 9 weeks. In another protocol, mice were fed a HFHC diet throughout the study.

Results: 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. In mice fed a HFHC throughout the study, azapeptides reduced lesion progression in the aortic vessel and sinus. The anti-atherosclerotic effect of azapeptides was associated with a reduced ratio of iNOS/CD206 macrophages within lesions, and lowered plasma inflammatory cytokine levels. Monocytes from azapeptide-treated mice showed altered mitochondrial oxygen consumption rates, consistent with an M2-like phenotype. These effects were dependent on CD36, and not observed in apoecd36 mice.

Conclusions: Azapeptides MPE-001 and MPE-003 diminished aortic lesion progression and reduced, below pre-existing levels, lesions in the aortic sinus of atherosclerotic mice. A relative increase of M2-like macrophages was observed in lesions, associated with reduced systemic inflammation. Development of CD36-selective azapeptide ligands merits consideration for treating atherosclerotic disease.