humanin and Hypercholesterolemia

Humanin (HN) is an endogenous mitochondrial-derived cytoprotective peptide that has shown protective effects against atherosclerosis and is expressed in human vessels. However, its effects on the progression of kidney disease are unknown. We hypothesized that HN would protect the kidney in the early phase of atherogenesis.. Forty-eight mice were studied in four groups (n=12 each). Twenty-four ApoE deficient mice were fed a 16-week high-cholesterol diet supplemented with saline or HN (4mg/kg/day, intraperitoneal). C57BL/6 mice were fed a normal diet supplemented with saline or HN. Microvascular architecture was assessed with micro-CT and vascular wall remodeling by alpha-SMA staining. The effects of HN on angiogenesis, inflammation, apoptosis and fibrosis were evaluated in the kidney tissue by Western blotting and histology.. Cortical microvascular spatial density and media/lumen area ratio were significantly increased in high-cholesterol diet fed ApoE deficient mice, but restored by HN. HN up-regulated the renal expressions of anti-angiogenic proteins angiostatin and TSP-1, and inhibited angiopoietin-1. HN attenuated inflammation by down-regulating MCP-1, TNF-alpha and osteopontin. HN also tended to restore pSTAT3 and attenuated Bax expression, suggesting blunted apoptosis. Kidney collagen IV expression was alleviated by HN treatment.. HN attenuates renal microvascular remodeling, inflammation and apoptosis in the early stage of kidney disease in hypercholesterolemic ApoE(-/-) mice. HN may serve as a novel therapeutic target to mitigate kidney damage in early atherosclerosis.

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Blotting, Western; Disease Progression; Female; Hypercholesterolemia; Inflammation; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Microvessels; Neovascularization, Pathologic

Humanin (HN) is a cytoprotective peptide derived from endogenous mitochondria, expressed in the endothelial layer of human vessels, but its role in atherogenesis in vivo is not known. In vitro study, however, HN reduced oxidized low-density lipoprotein induced formation of reactive oxygen species and apoptosis. The present study tested the hypothesis that long term treatment with HN will have a protective role against endothelial dysfunction and progression of atherosclerosis in vivo.. Daily intraperitonial injection of the HN analogue HNGF6A for 16 weeks prevented endothelial dysfunction and decreased atherosclerotic plaque size in the proximal aorta of ApoE-deficient mice fed on a high cholesterol diet, without showing direct vasoactive effects or cholesterol-reducing effects. HN was expressed in the endothelial layer on the aortic plaques. HNGF6A treatment reduced apoptosis and nitrotyrosine immunoreactivity in the aortic plaques without affecting the systemic cytokine profile. HNGF6A also preserved expression of endothelial nitric oxide synthase in aorta.. HN may have a protective effect on endothelial function and progression of atherosclerosis by modulating oxidative stress and apoptosis in the developing plaque.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cholesterol, Dietary; Disease Progression; Female; Hypercholesterolemia; Intracellular Signaling Peptides and Proteins; Mice; Plaque, Atherosclerotic