Growth Hormone-Releasing Peptide-2 Suppresses Vascular Oxidative Stress in ApoE−/− Mice But Does Not Reduce Atherosclerosis

GH-releasing peptide-2 (GHRP-2) is a synthetic peptide that increases circulating GH and IGF-I levels. It also binds to CD36, a scavenger receptor for oxidized low-density lipoprotein (OxLDL), and may prevent cellular uptake of this proatherogenic complex. To determine its potential antiatherogenic effects, GHRP-2 (20 microg twice daily) was administered sc to ApoE(-/-) mice for 12 wk. GHRP-2 increased circulating IGF-I 1.2- to 1.6-fold and decreased circulating interferon-gamma by 66%. Although GHRP-2 did not alter atherosclerotic plaque area, it decreased aortic production of superoxide as assessed by dihydroethidium staining. GHRP-2 decreased aortic gene expression of 12/15-lipoxygenase by 92% and reduced the aortic expression of interferon-gamma and macrophage migration inhibitory factor. In cultured aortic smooth muscle cells, GHRP-2 prevented the OxLDL-induced generation of peroxides, down-regulation of IGF-I receptor, and apoptosis. In macrophages, GHRP-2 reduced lipid accumulation with OxLDL exposure. In summary, GHRP-2 exerts antioxidant effects in vivo and in vitro but does not reduce plaque burden. The lack of an antiatherogenic effect may be due to GH-dependent effects in vivo, thereby blunting the effect of increased IGF-I.