Humanin and its Potential in Cardiovascular Research
Humanin and its Potential in Cardiovascular Research
Research suggests that the naturally occurring micro-peptide Humanin may be encoded in the mitochondrial DNA, which is thought to be present only in mitochondria, suggesting that Humanin may exhibit unique properties.
Researchers have hypothesized that this peptide may protect cells against the complex process of apoptosis (also known as programmed cell death) to carry out its biological tasks.
This defense mechanism may prevent the Bcl2-associated X protein (Bax) from functioning normally.
[i] Humanin has been the subject of extensive study for its potential to protect neural tissue, cardiac muscle, the eye's retina, and the endothelial lining of blood vessels.
Humanin and A42 have been hypothesized to operate as chemoattractants for monocytes, possibly activating microglia via the G protein-coupled formylpeptide-like-1 receptor (FPRL1).
Humanin, however, has been posited to stop A42 from building up within cells. Humanin has been implicated in various cellular functions, and some studies have even suggested that it may interact directly with the FPRL1 and FPRL2 receptors and the STAT signaling pathway.
Phagocytic cells seem to express FPRL1 and FPRL2 receptors, whereas neurons may use other receptors, suggesting that different cell types may use separate receptors to react to Humanin.
Humanin may interact with A directly, outside of receptor-mediated pathways, to change the shape of A aggregates.
Importantly, Humanin may have contrasting effects on insulin/IGF signaling in various tissues, promoting signaling in primary neurons while perhaps having a distinct effect on the heart, as suggested in research studies conducted on murine models.
Research suggests that the peptide may inhibit downstream signaling and prevent apoptosis by interacting with important pro-apoptotic-apoptotic proteins such as BAX, tBID, and BimEL.
Despite some inconsistencies in the published literature, which may likely be attributed to differences in cell types and experimental settings, these results point to the proposed complexity and variety of Humanin's protective potential. [ii]
Research in rats suggests that Humanin may have anti-apoptosis and other programmed cell death protective properties. Humanin may protect neurons in neurodegenerative illnesses, where it is thought to prevent cell death caused by beta-amyloid plaque buildup.
[iii] Additionally, studies have suggested that Humanin may prevent excitotoxic neuronal death from NMDA pulses. [iv]
Similar results were found when looking at neuronal death due to prion illness.
[v] These findings suggest that Humanin may possibly impede the development of neurodegenerative diseases. Research study authors noted: "amyloidogenic peptides can induce prolonged activation of pro-apoptotic-apoptotic marker expression in cultured neurons even at sublethal concentrations.”
In neurodegenerative illnesses, these consequences may exacerbate vulnerability to further metabolic insults and lead to persistent neuronal dysfunction. If this is the case, mitigation techniques directed against neuronal caspase activation in the early stages of AD and prion disorders might be effective.
[vi] Humanin has been suggested to protect neurons via two separate methods, which work to stop the mitochondrial apoptotic pathway from being activated.
Normal cell death and recycling are orchestrated by a cascade of caspases signaled by the Bcl-2 family of proteins to release proteins from the mitochondrial membrane.
Despite its importance in many situations, such as viral invasions, its dysregulation in disease states may cause widespread and erratic cell death.
There is speculation that Humanin may bind to the Bcl-2 boosting proteins Bid and tBid, possibly inhibiting their activity and preventing the onset of apoptosis. [vii]
Findings imply that Humanin is a protein that may preserve synapses in the hippocampus when released by astrocytes.
A drop in Humanin's function with age has been linked to age-related memory loss and increased vulnerability to neurodegenerative disorders in specific laboratory test models
[viii], as suggested by research conducted in the context of certain regulating systems.
Humanin's expression and protective potential in vasculature have been hypothesized by recent research, suggesting that the protein is present in the lining of blood arteries and may play an important role in protecting against the harmful effects of oxidized low-density lipoprotein (LDL) cholesterol.
In particular, research suggests that Humanin might prevent oxidative stress from leading to the generation of reactive oxygen species (free radicals) by interfering with LDL oxidation.
Humanin has been suggested to decrease the vasculature's apoptosis and reactive oxygen species by up to 50%.
[ix] Further, data suggests that Humanin levels may decrease with age, and new results purport that certain illness states may potentially affect Humanin levels.
Finding blood indicators that may objectively measure mitochondrial activity in the setting of cardiovascular disease has been a long-standing goal of cardiology researchers.
These indicators are essential for assessing the well-being of cardiac disease model organisms in experimental settings, as they provide:
Information on the degree of tissue ischemia
The rate of disease development
The need for intervention
As suggested by studies done in Russia, Humanin levels appear to decrease proportionately with the severity of cardiovascular disease, suggesting they may serve as a promising marker in this respect. [x]
The retinal pigment epithelium (RPE) is a layer of specialized cells in the retina that performs several important activities, such as absorbing and reflecting light, filtering blood components, and protecting the eye's immune-privileged status.
Humanin's potential importance in the RPE has been suggested by recent studies, emphasizing its potential involvement in lowering oxidative stress in this ocular tissue.
In cell culture trials, Humanin was posited to improve RPE functioning and its resistance to apoptosis, the programmed cell death. [xi]
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[i] Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity.
FASEB J. 2002 Aug;16(10):1331-3. doi: 10.1096/fj.02-0018fje. Epub 2002 Jun 21. PMID: 12154011. https://pubmed.ncbi.nlm.nih.gov/12154011/
[ii] Yen K, Lee C, Mehta H, Cohen P. The emerging role of the mitochondrial-derived peptide Humanin in stress resistance. J Mol Endocrinol. 2013 Jan 11;50(1):R11-9. doi: 10.1530/JME-12-0203. PMID: 23239898; PMCID: PMC3705736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705736/
[iii] Matsuoka M. Humanin; a defender against Alzheimer’s disease? Recent Pat CNS Drug Discov. 2009 Jan;4(1):37-42. doi: 10.2174/157488909787002609. PMID: 19149712. https://pubmed.ncbi.nlm.nih.gov/19149712/
[iv] Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity.
FASEB J. 2002 Aug;16(10):1331-3. doi: 10.1096/fj.02-0018fje. Epub 2002 Jun 21. PMID: 12154011. https://pubmed.ncbi.nlm.nih.gov/12154011/
[v] Xu X, Chua CC, Gao J, Chua KW, Wang H, Hamdy RC, Chua BH. Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway.
Brain Res. 2008 Aug 28;1227:12-8. doi: 10.1016/j.brainres.2008.06.018. Epub 2008 Jun 16. PMID: 18590709; PMCID: PMC2575816. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575816/
[vi] White AR, Guirguis R, Brazier MW, Jobling MF, Hill AF, Beyreuther K, Barrow CJ, Masters CL, Collins SJ, Cappai R. Sublethal concentrations of prion peptide PrP106-126 or the amyloid beta peptide of Alzheimer’s disease activates expression of proapoptotic markers in primary cortical neurons.
Neurobiol Dis. 2001 Apr;8(2):299-316. doi: 10.1006/nbdi.2001.0386. PMID: 11300725. https://pubmed.ncbi.nlm.nih.gov/11300725/
[vii] Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, Reed JC. Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. J Biol Chem.
2005 Apr 22;280(16):15815-24. doi: 10.1074/jbc.M411902200. Epub 2005 Jan 20. PMID: 15661737. https://pubmed.ncbi.nlm.nih.gov/15661737/
[viii] Zárate SC, Traetta ME, Codagnone MG, Seilicovich A, Reinés AG. Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons.
Front Aging Neurosci. 2019 May 31;11:123. doi: 10.3389/fnagi.2019.00123. PMID: 31214013; PMCID: PMC6555273. https://pubmed.ncbi.nlm.nih.gov/31214013/
[ix] Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, Lerman LO, Pagano RE, Cohen P, Lerman A. Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress.
Cardiovasc Res. 2010 Nov 1;88(2):360-6. doi: 10.1093/cvr/cvq191. Epub 2010 Jun 18. PMID: 20562421; PMCID: PMC2952532. https://pubmed.ncbi.nlm.nih.gov/20562421/
[x] Cai H, Liu Y, Men H, Zheng Y. Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases.
Front Endocrinol (Lausanne). 2021 Jun 10;12:683151. doi: 10.3389/fendo.2021.683151. PMID: 34177809; PMCID: PMC8222669. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222669/
[xi] Sreekumar, Parameswaran & Ishikawa, Keijiro & Spee, Chris & Mehta, Hemal & Wan, Junxiang & Yen, Kelvin & Kannan, Ram & Hinton, David. (2016).
The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Investigative Opthalmology & Visual Science. 57. 1238. 10.1167/iovs.15-17053.
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