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

• Published in: Atherosclerosis Vol. 307; pp. 52 - 62
• Main Authors: Frégeau, Geneviève, Sarduy, Roger, Elimam, Hanan, Esposito, Cloé L., Mellal, Katia, Ménard, Liliane, Leitão da Graça, Silas D., Proulx, Caroline, Zhang, Jinqiang, Febbraio, Maria, Soto, Yosdel, Lubell, William D., Ong, Huy, Marleau, Sylvie
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.08.2020
• Subjects: Atherosclerosis; Azapeptides; CD36; Macrophages; Regression; Regression; Azapeptides; CD36; Macrophages; Atherosclerosis
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2020.06.010

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. 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-Tyr4]-GHRP-6) or MPE-003 ([aza-(N,N-diallylaminobut-2-ynyl)Gly4]-GHRP-6) for 9 weeks. In another protocol, mice were fed a HFHC diet throughout the study. 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 apoe−/−cd36−/− mice. 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. [Display omitted] •Azapeptide analogs of GHRP-6 were synthesized as selective CD36 ligands.•Azapeptides elicit lesion regression in aortic sinus in a CD36-dependent manner.•Azapeptides halted atherosclerotic lesion development in aorta.•Azapeptides induce macrophage skewing towards the anti-inflammatory phenotype.