Evaluation of growth hormone-releasing peptide-2 as a potential therapy for atherosclerosis
Description
Growth Hormone-Releasing Peptide-2 (GHRP-2) is a synthetic peptide that increases circulating Growth Hormone and Insulin-Like Growth Factor-1 (IGF-1) levels. It also binds to CD36, a scavenger receptor for oxidized low-density lipoprotein (OxLDL), and may prevent cellular uptake of this proatherogenic lipoprotein complex. This study was conducted to determine whether GHRP-2 would be a suitable antiatherogenic therapy in vivo by reducing inflammation, oxidative stress, apoptosis of vascular cells, and lipid accumulation. Additionally, in vitro studies were performed to see if GHRP-2 could inhibit some of the above effects in cultured aortic smooth muscle cells and macrophages exposed to OxLDL. GHRP-2 was administered subcutaneously to ApolipoproteinE knockout mice, a hypercholesterolemic animal model of atherosclerosis. GHRP-2 treatment caused an increase in circulating IGF-1 levels and a decrease in circulating interferon-gamma (IFN-gamma). While GHRP-2 treatment did not alter atherosclerotic plaque area, there was a robust decrease in aortic production of superoxide in mice treated with GHRP-2. Consistent with this decrease in oxidative stress, GHRP-2 treatment caused a 12 fold decrease in aortic expression of 15-lipoxygenase. There was also a trend for GHRP-2 treatment to increase the amount of macrophages and decrease the number of apoptotic cells in atherosclerotic plaques in the aortic valve area. Additionally, GHRP-2 treatment reduced the aortic expression of IFN-gamma, Cu/Zn superoxide dismutase, macrophage migration inhibitory factor, and IGF-1 receptor (IGF-1R). In cultured human aortic smooth muscle cells, GHRP-2 treatment prevented the OxLDL-induced generation of peroxides and downregulation of IGF-1R. GHRP-2 also rescued aortic smooth muscle cells from OxLDL-induced apoptosis. Additionally, GHRP-2 reduced lipid accumulation in cultured macrophages exposed to OxLDL. In conclusion, GHRP-2 exerts antioxidant and antiapoptotic effects both in vivo and in vitro. The net result of GHRP-2 treatment in vivo seems to be neutral in terms of total atherosclerotic plaque burden. This lack of an antiatherogenic effect could be due to the inability of GHRP-2 to prevent OxLDL-induced downregulation of the IGF-1R in vivo, thereby blunting the effect of increased IGF-1