Hexarelin reduces atherosclerotic plaques by inhibiting macrophage oxidized-LDL uptake in ApoE-/- mice
Background
Growth hormone secretagogues (GHS) are known to have protective effects on the cardiovascular system. However, their specific benefits for macrophage function in the context of atherosclerosis (AS) have been poorly understood. Atherosclerosis involves the uptake of oxidized low-density lipoprotein (ox-LDL) by macrophages, leading to foam cell formation and plaque development, a process mediated by scavenger receptors like LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1). The activation of the NF-κB signaling pathway is a critical step in this inflammatory cascade. This study investigates hexarelin, a synthetic peptidyl GHS, to clarify its potential role in modulating macrophage activity to suppress the progression of AS, targeting a key mechanism of the disease.
Study Design
Atherosclerosis was induced in ApoE-/- mice by feeding them a high-lipid diet for 3 months. One group of mice (AS + Hex) received daily subcutaneous injections of hexarelin (100 μg/kg) for the duration of the study. The control group (AS) received saline injections. Age-matched C57BL/6J mice on a normal diet served as healthy controls. Researchers used histological staining, ELISA, western blotting, confocal microscopy, and flow cytometry to assess atherosclerotic plaque formation, lipid profiles, and related signaling molecules in aortic tissues and RAW264.7 macrophage cell lines.
Results
Compared to the saline-treated AS group, hexarelin administration significantly attenuated the development of atherosclerosis. The treatment improved the circulatory lipid profile, decreasing serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c), while increasing high-density lipoprotein cholesterol (HDL-c). Histological analysis revealed that hexarelin reduced the formation of atherosclerotic plaques and neointima. Mechanistically, hexarelin decreased the aortic expression of the macrophage marker CD68 and the scavenger receptor LOX-1. > In both the aorta of ApoE-/- mice and in RAW264.7 macrophages, hexarelin suppressed ox-LDL uptake, inhibited LOX-1 expression, and suppressed the activation of the nuclear factor-kappa B (NF-κB) signaling pathway. It also increased the expression of the growth hormone secretagogue receptor (GHSR).
Key Findings
- Hexarelin attenuated atherosclerotic plaque and neointima formation in ApoE-/- mice after 3 months of treatment.
- The peptide improved serum lipid profiles by decreasing TC, TG, and LDL-c while increasing HDL-c.
- Hexarelin decreased aortic expression of macrophage marker CD68 and scavenger receptor LOX-1.
- Hexarelin inhibited macrophage uptake of ox-LDL by suppressing the LOX-1-NF-κB signaling pathway in both aorta and RAW264.7 cells.
- Hexarelin treatment was associated with increased expression of the GHSR receptor in the aorta of treated mice.
Why It Matters
This research provides a mechanistic basis for hexarelin's cardioprotective effects, specifically highlighting its role in modulating macrophage behavior—a key driver of atherosclerotic plaque formation. For peptide users or researchers, this suggests hexarelin may offer benefits beyond growth hormone release, directly targeting the inflammatory processes of cardiovascular disease. The study supports the potential use of hexarelin as a therapeutic agent against atherosclerosis. While promising, this is an early-stage animal study. Clinical translation would require extensive human trials to establish safety, efficacy, and appropriate dosing protocols for preventing or treating cardiovascular disease in humans. The findings suggest hexarelin could be a valuable component in a multifaceted approach to managing cardiovascular risk, particularly by improving lipid metabolism and reducing vascular inflammation.
