Humanin prevents intra-renal microvascular remodeling and inflammation in hypercholesterolemic ApoE deficient mice

Zhang, Xin; Urbieta-Caceres, Victor H.; Eirin, Alfonso; Bell, Caitlin C.; Crane, John A.; Tang, Hui; Jordan, Kyra L.; Oh, Yun Kyu; Zhu, Xiang Yang; Korsmo, Michael J.; Bachar, Adi R.; Cohen, Pinchas; Lerman, Amir; Lerman, Lilach O.

doi:10.1016/j.lfs.2012.07.010

Cited by 53 publications

(45 citation statements)

References 33 publications

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“…Therefore, humanin could potentially be used as a marker for mitochondrial function in cardiovascular disease or as a treatment strategy to stabilize atherosclerosis in patients found to have endothelial dysfunction. In support of this stipulation, prior work in animal models supports the ability of humanin to ameliorate early vascular disease in hyperlipidemic mice (30). Indeed, given the few differences observed between patients with normal endothelial function and those with endothelial dysfunction the underlying mechanisms linking humanin to endothelial function remain to be elucidated, especially in view of the limited associations we found between humanin levels and other inflammatory mediators commonly associated with regulation of endothelial function such as L-arginine, insulin, homocysteine, hs-CRP, fibrinogen, lipoprotein (a), or lipids.…”

Section: Discussionmentioning

confidence: 80%

“…This observation is somewhat intriguing considering the abundant data indicating that humanin reduces inflammation. Based on prior work (30), one would surmise that humanin levels would be associated with oxidative stress, which should reduce cellular inflammatory responses. Possibly, in patients with elevated numbers of leukocytes who are predisposed to develop endothelial dysfunction, humanin increases as a defense mechanism stabilizing previously unstable disease.…”

Section: Discussionmentioning

confidence: 99%

“…Possibly, in patients with elevated numbers of leukocytes who are predisposed to develop endothelial dysfunction, humanin increases as a defense mechanism stabilizing previously unstable disease. This view is underscored by recent in vivo work showing that in the renal vasculature of an atherosclerotic murine model the expression of MCP-1 and osteopontin, which both induce an influx of inflammatory cells such as monocytes/macrophages into the endothelium, were reduced after 16 wk of intraperitoneal injections of humanin (30). Thus it is not unlikely that humanin serves to stabilize the endothelium by negating the potential wayward consequences of vascular inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…These effects are believed to be achieved through improved nitric oxide (NO) bioavailability (22), regulation of anti-apoptotic factors (19), and AMP-kinase signaling (21). Recent work has also shown that humanin attenuates remodeling of the renal vasculature in a murine model of atherosclerosis mainly by downregulating proteins involved in angiogenesis, apoptosis, fibrosis, and inflammation (30). Taken together, preclinical data suggest beneficial structural and functional effects of humanin on the vascular system; however, there is a paucity of data on the functional correlation in humans.…”

mentioning

confidence: 99%

“…While humanin expression in the endothelium and in atherosclerotic plaques, and its ability to alleviate the deleterious effects of ROS-induced endothelial injury (21,22) as well as inflammation (30) in animal models, are well documented, it is unknown if circulating endogenous levels of humanin are linked to endothelial dysfunction in humans. The aim of this study was to test the hypothesis that coronary endothelial dysfunction is associated with altered humanin levels in humans.…”

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confidence: 99%

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Circulating humanin levels are associated with preserved coronary endothelial function

Widmer

Flammer

Herrmann

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

104

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Humanin is a small endogenous antiapoptotic peptide, originally identified as protective against Alzheimer's disease, but subsequently also found on human endothelium as well as carotid artery plaques. Endothelial dysfunction is a precursor to the development of atherosclerotic plaques, which are characterized by a highly proinflammatory, reactive oxygen species, and apoptotic milieu. Previous animal studies demonstrated that humanin administration may improve endothelial function. Thus the aim of this study was to test the hypothesis that patients with coronary endothelial dysfunction have reduced systemic levels of humanin. Forty patients undergoing coronary angiography and endothelial function testing were included and subsequently divided into two groups based on coronary blood flow (CBF) response to intracoronary acetylcholine (normal ≥ 50% increase from baseline, n = 20 each). Aortic plasma samples were obtained at the time of catheterization for the analysis of humanin levels and traditional biomarkers of atherosclerosis including C-reactive protein, Lp-Pla(2), and homocysteine. Baseline characteristics were similar in both groups. Patients with coronary endothelial dysfunction (change in CBF = -33 ± 25%) had significantly lower humanin levels (1.3 ± 1.1 vs. 2.2 ± 1.5 ng/ml, P = 0.03) compared with those with normal coronary endothelial function (change in CBF = 194 ± 157%). There was a significant and positive correlation between improved CBF and humanin levels (P = 0.0091) not seen with changes in coronary flow reserve (P = 0.76). C-reactive protein, Lp-Pla(2), and homocysteine were not associated with humanin levels. Thus we observed that preserved human coronary endothelial function is uniquely associated with higher systemic humanin levels, introducing a potential diagnostic and/or therapeutic target for patients with coronary endothelial function.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Circulating humanin levels are associated with preserved coronary endothelial function

Widmer

Flammer

Herrmann

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

104

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MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

Benayoun

Lee

2019

BioEssays

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Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome‐bearing organelles would likely include gene expression regulation. Multiple nuclear‐encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial‐encoded factors are known to actively regulate nuclear gene expression. MOTS‐c (mitochondrial open reading frame of the 12S ribosomal RNA type‐c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS‐c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene‐encoded factors that cross‐regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator.

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Humanin binds MPP8: mapping interaction sites of the peptide and protein

Maximov

Martynenko

Arman

et al. 2013

Journal of Peptide Science

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Humanin (HN), a 24-amino acid peptide encoded by the mitochondrial 16S rRNA gene, was discovered by screening a cDNA library from the occipital cortex of a patient with Alzheimer's disease (AD) for a protection factor against AD-relevant insults. Earlier, using the yeast two-hybrid system, we have identified the M-phase phosphoprotein 8 (MPP8) as a binding partner for HN. In the present work, we further confirmed interaction of HN with MPP8 in co-immunoprecipitation experiments and localized an MPP8-binding site in the region between 5 and 12 aa. of HN. We have also shown that an MPP8 fragment (residues 431-560) is sufficient to bind HN. Further studies on functional consequences of the interaction between the potential oncopetide and the oncoprotein may elucidate some aspects of the molecular mechanisms of carcinogenesis.

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Humanin prevents intra-renal microvascular remodeling and inflammation in hypercholesterolemic ApoE deficient mice

Cited by 53 publications

References 33 publications

Circulating humanin levels are associated with preserved coronary endothelial function

Circulating humanin levels are associated with preserved coronary endothelial function

MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

Humanin binds MPP8: mapping interaction sites of the peptide and protein

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