Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice

Department of Internal Medicine, Divisions of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States.
Atherosclerosis (Impact Factor: 3.99). 06/2011; 219(1):65-73. DOI: 10.1016/j.atherosclerosis.2011.06.038
Source: PubMed


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.

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    • "Recent years there are a few studies found that HN was associated with preserved endothelial function and might prevent plaque progression [5] [23]. Our data claims that HN has a protective effect on the HG-induced apoptosis of HUVECs for the first time, but more specific mechanisms need further researches. "
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    ABSTRACT: Aims Humanin (HN) is known for its anti-apoptotic functions in neuronal cells. In this study, we sought to investigate the protective effect of [Gly14]-Humanin (HNG) in high glucose (HG)-induced apoptosis of human umbilical vein endothelial cells (HUVECs). Methods 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to examine cell viability, DNA chromatin morphology was assessed using Hoechst 33342 staining, and the generation of intracellular reactive oxygen species (ROS) was assessed using the fluorescent probe dichlorofluorescein diacetate (DCFH-DA). The expression of poly ADP-ribose polymerase (PARP), the pro-apoptotic protein bax and the anti-apoptotic protein bcl-2 were examined using western blot analysis. The mRNA level of bax and bcl-2 were detected by quantitative Real-Time PCR. Results Compared with treatment with HG 72 h, pretreatment with HNG for 3 h significantly increased cell viability (P < 0.001), reduced nuclear fluorescence of HUVECs (P < 0.05), the levels of cleaved PARP (P < 0.05), ROS formation (P < 0.05) and the ratio of bax/bcl-2 (P < 0.05) compared with treatment with HG for 72 h. Quantitative Real-Time PCR showed that mRNA level of bax reduced (P < 0.05) and mRNA level of bcl-2 increased (P < 0.05) after pretreatment with HNG. Conclusions Our results imply that HNG can protect HUVECs from apoptosis induced by HG through the bax/bcl-2 pathway.
    Diabetes Research and Clinical Practice 10/2014; 106(3). DOI:10.1016/j.diabres.2014.09.020 · 2.54 Impact Factor
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    • "Notably, Ames dwarf mice exhibit much reduced levels of mtDNA damage and higher levels of circulating HN compared to their controls (Sanz et al., 2002). It is also interesting to note that certain age-related diseases, such as atherosclerosis, are associated with a reduction of HN levels in human subjects, a fact that may contribute the mechanism by which it is associates with longer lifespan in mice (Oh et al., 2011). "
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    ABSTRACT: Aging is influenced by endocrine pathways including the growth hormone/insulin-like growth factor-1 (GH/IGF) axis. Mitochondrial function has also been linked to the aging process, but the relevant mitochondrial signals mediating the effects of mitochondria are poorly understood. Humanin is a novel signaling peptide that acts as a potent regulator of cellular stress responses and protects from a variety of in vitro and in vivo toxic and metabolic insults. The circulating levels of humanin decline with age in mice and humans. Here, we demonstrate a negative correlation between the activity of the GH-IGF axis and the levels of humanin, as well as a positive correlation between humanin and lifespan in mouse models with altered GH/IGF-I axis. Long-lived, GH-deficient Ames mice displayed elevated humanin levels, while short-lived GH-transgenic mice have reduced humanin levels. Furthermore, treatment with GH or IGF-I reduced circulating humanin levels in both mice and human subjects. Our results indicate that GH and IGF are potent regulators of humanin levels and that humanin levels correlate with lifespan in mice. This suggests that humanin represents a circulating mitochondrial signal that participates in modulating the aging process, adding a coordinated mitochondrial element to the endocrine regulation of aging.
    Aging cell 07/2014; 13(5). DOI:10.1111/acel.12243 · 6.34 Impact Factor
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    • "An in vitro study found that humanin was able to protect endothelial cells from oxidative stress induced by oxidized LDL (Bachar et al. 2010). An in vivo follow-up on that observation demonstrated that HNG was able to improve cardiovascular function in Apoe-deficient mice placed on a high-cholesterol diet (Oh et al. 2011). Combining these data suggests that the increased levels of humanin found in atherosclerotic plaques are a protective response to stress and that humanin may be able to protect against oxidative stress. "
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    ABSTRACT: The discovery of humanin, a novel, mitochondria-derived peptide, has created a potentially new category of biologically active peptide. As more research unravels the endogenous role of humanin as well as its potential pharmacological use, its role in stress resistance has become clearer. Humanin protects cells from oxidative stress, serum starvation, hypoxia, and other insults in vitro and also improves cardiovascular disease as well as Alzheimer's disease in vivo. In this review we discuss the emerging role of humanin in stress resistance and its proposed mechanism of action.
    Journal of Molecular Endocrinology 12/2012; 50(1). DOI:10.1530/JME-12-0203 · 3.08 Impact Factor
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