Jci adipocytesecreted exosomal microrna34a inhibits m2. Pi3kregulated mirnas mir34a, mir34 family, mir652, and mir154 was associated with favorable cardiac function, decreased fibrosis andor increased angiogenesis in mouse models of pressure overload andor myocardial infarction mi bernardo et al. Regulation of microrna expression and function by nuclear. Mir 34a was reported to serve an important role in cardiac fibrosis in patients and in mice, and it has been suggested that therapeutic inhibition of members of the mir34 family may attenuate pathological cardiac remodeling and improve cardiac function in patients, as this approach has been proven to be effective in mouse models of cardiac. Small molecules that restore the expression of growthinhibitory micrornas mirna downregulated in tumors may have potential as anticancer agents. Accordingly, mir34a may play a key role in agerelated susceptibility to oxidative stress in arpe19 cells by targeting the sirt1p66shc pathway, leading to amd. Dihydromyricetin prevents diabetic cardiomyopathy via mir. A rat model of myocardial hypertrophy was used and confirmed by heart. Sirt1 is a mir 34a target gene in endothelial cells. Microrna profiling implicates the insulinlike growth factor pathway in bleomycininduced pulmonary fibrosis in mice. Stem cells are undifferentiated cells and have multilineage differentiation potential. Cabili mn, trapnell c, goff l, koziol m, tazonvega b, regev a, rinn jl. The therapeutic potential of mirnas regulated in settings.
Molecular interplay between microrna34a and sirtuin1 in. We sought to compare the effectiveness of mscs and mscderived exosomes mscexo in repairing infarcted hearts and to identify how mscexo mediated cardiac repair is regulated. Moreover, mir 34a can target multiple molecules to regulate m1m2 polarization phenotype of macrophages 8,9. Mesenchymal stem cell mscbased therapies have had positive outcomes both in animal models of cardiovascular diseases and in clinical patients. Microrna34a regulates the longevityassociated protein sirt1. The proaging mirna, mir34a, is hyperactivated in the cardiac myocardial tissues of patients and mice with diabetes, leading to diabetic cardiomyopathy dcm. Noncoding rnas in cardiac aging fulltext cellular physiology. Micrornas as modulators of longevity and the aging process. This study investigated altered mirna expression and autophagic activity in pathogenesis of cardiac hypertrophy. Cardiac fibrosis is a crucial factor of heart failure.
Mar 07, 20 we propose that altered expression of mirnas in the heart during ageing contributes to the agedependent decline in cardiac function. Cited2 has been implicated in the regulation of heart development. Together, these results identify ageinduced expression of mir 34a and inhibition of its target pnuts as a key mechanism that regulates cardiac contractile function during ageing and after acute. The therapeutic potential of mirnas regulated in settings of. Lechner s, seeger t, fischer a, heydt s, kaluza d, treguer k, carmona g, bonauer a. Microrna21 contributes to myocardial disease by stimulating map kinase signalling in fibroblasts. Bu, shen, and colleagues find that intestinal and colon stem cells, primarily undergoing symmetric division, under conditions of inflammatory stress increase their rate of asymmetric cell division. Mildtomoderate overexpression of sirt1 reduces cardiac hypertrophy and cardiomyocyte apoptosis and improves contractile function in aged mice. Upregulated sirtuin 1 by mirna34a is required for smooth. Micrornas mirna are evolutionary highly conserved noncoding rna molecules, exerting essential functions in a wide range of physiological. Upregulated sirtuin 1 by mirna 34a is required for smooth muscle cell differentiation from pluripotent stem cells. Sirt1 mediates the effects of mir 34a upon cell senescence in endothelial cells. In a rat myocardial infarction model, we found that mscexo inhibited cardiac fibrosis, inflammation, and improved cardiac function.
Novel molecular therapeutic targets in cardiac fibrosis. Microrna34a regulation of endothelial senescence sciencedirect. Cardiac fibrosis is increasingly recognized as a common final pathway in advanced heart diseases. Research highlights microrna 34a mir 34a regulates senescence and cell cycle progression in endothelial cells. It has been reported that several micrornas mirnas, mirs were involved in cardiac fibrosis, however, the role and possible regulatory mechanism of microrna5a mir5a in cardiac fibrosis have not been investigated. Here we show that mir 34a is induced in the ageing heart and that in vivo silencing or genetic deletion of mir 34a reduces age associated cardiomyocyte cell death. Heart failure is a major cause of mortality in humans. Microribonucleic acids mirnas are in the spotlight as posttranscriptional regulators of gene expression. Expression of microrna34a in alzheimers disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Inhibition of mir34a improves cardiac function in adult hearts post mi. Alternative mechanisms of mir34a regulation in cancer cell death. Developing mirna therapeutics for cardiac repair in.
Cardiospheres css are selfassembling multicellular clusters from the cellular outgrowth from cardiac explants cultured in nonadhesive substrates. Developing mirna therapeutics for cardiac repair in ischemic heart disease. Increasing evidence suggests that dihydromyricetin dhm can be used to effectively treat cardiomyopathy. Along similar lines, inhibition of mir 34a improved cardiac function after mi in mice, attenuating cardiomyocyte apoptosis and telomere shortening. In particular, mir34a modulates several important target proteins involved in cell cycle, apoptosis, senescence and differentiation. Microrna34a regulates cardiac ageing and function pubmed. Roles of microrna34a targeting sirt1 in mesenchymal stem. Mirnasequence indicates that mesenchymal stem cells and.
Moreover, mir34a can target multiple molecules to regulate m1m2 polarization phenotype of macrophages 8,9. In isolated cardiomyocytes, we found that mir34a directly regulated cell cycle activity. In this study, we investigated whether dhm affects the expression of mir34a in dcm. In the present study, we aimed to determine whether the expression levels of circulating mirnas in serum were changed with aging or sex. Microrna 34a regulates cardiac ageing and function. Diabetes induces the activation of proageing mir34a in the.
To determine whether antagonizing mir34a enhances cardiac regeneration in adult hearts, lnabased antimir34a lna34a or scrambled negative control was delivered intravenously at 6 hours and 2 days after mi in adults online figure iva. A smallmolecule modulator of the tumorsuppressor mir34a. Cardiovascular diseases are one of the most common causes of death in humans and are responsible for billions of dollars in health care expenditures. Genetic deficiency of mir34a protected ageinginduced cardiac dysfunction, but overexpression of myocyte mir155 was linked to protection from necrotic cell death in vitro 16,17. They further reveal that the tumor suppressor mir34a together with numb and notch form a feedforward loop that curbs excessive proliferation by enforcing binary cell fate choice and that disrupting. For full access to this pdf, sign in to an existing account, or purchase an annual. Jul 11, 2019 micrornas mirnas are short, noncoding rnas that posttranscriptionally repress translation or induce mrna degradation of target transcripts through sequencespecific binding. Bagchi c a faculty of medicine, university of toronto, toronto, on m5s 1a8, canada b department of human anatomy and cell science, university of manitoba, winnipeg, mb r3t 2n2, canada. Myocardial infarctioninduced micrornaenriched exosomes. Therefore, if possible, rnaseq should be used to find out the mir34a target genes in order to clarify the inhibition effect of adipocytesecreted exosomal microrna34a on m2 macrophage polarization. Microrna34a regulates cardiac ageing and functionboon et alnature. Microrna 34a regulates cardiac ageing and function 20 february 20 nature, vol. The framingham heart study and the baltimore longitudinal study on aging blsa have shown that, in healthy individuals without concomitant cardiovascular diseases, aging results in an increase in the prevalence of left ventricular lv hypertrophy, a decline in diastolic function, and relatively preserved systolic function at rest but a decline in. Seminal work has recently demonstrated that mir34a is induced in the ageing heart and in vivo silencing or genetic deletion of mir34a reduces ageassociated cardiomyocyte cell death.
Frontiers involvement of microrna34a in agerelated. Antiaging treatment has the potential to prevent the development of ischemic injury and improves cardiac function. Pdf microrna34a regulates cardiac ageing and function. Microrna34a plays a key role in cardiac repair and. Diabetes induces the activation of proageing mir34a in. Microrna profiling implicates the insulinlike growth. Ageing is one of the most complex processes in nature. Cited2 regulates proliferation and survival in young and old. Selected serum microrna, abdominal aortic calcification. Old ocscs showed decreased differentiation and proliferation capacities as compared to young ycscs, the. Moreover, mir34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Aug 01, 20 mildtomoderate overexpression of sirt1 reduces cardiac hypertrophy and cardiomyocyte apoptosis and improves contractile function in aged mice.
The authors identified phosphatase 1 nuclear targeting subunit pnuts as a novel direct target of mir 34a and detected downregulation of pnuts in the aged heart. Article information, pdf download for mir34a and mir9 are. However, whether mir194 participates in the process of. Pdf microrna34a regulates cardiac aging and function. We propose that altered expression of mirnas in the heart during ageing contributes to the age dependent decline in cardiac function. Several endothelialspecific mirnas have been identified as regulators of cardiac and endothelial function and linked to the regulation of angiogenesis and the development of senescence and inflammation. Mesenchymal stem cells mscs repair infarcted heart through paracrine mechanism. They further reveal that the tumor suppressor mir 34a together with numb and notch form a feedforward loop that curbs excessive proliferation by enforcing binary cell fate choice and that disrupting. We measured telomere length, tissue activity of telomerase, mrna levels of telomerase reverse transcriptase tert and telomerase rna component terc, and expression of the telomeric regulator microrna mir34a. Mir34a was reported to serve an important role in cardiac fibrosis in. Harnessing the therapeutic potential of micrornas for.
In contrast, microrna27a, microrna28a, and microrna34a were significantly enriched in exosomes derived from tnf. Context microrna mirna regulate posttranscriptionally the expression of osteogenesis and angiogenesis associated genes and emerge as potential noninvasive biomarkers in vascular and bone diseases. Meanwhile, one study have indicated circulating mir34a level closely correlated with heart failure. This includes the potential of mirnas as therapeutic targets in cardiac and vascular. The molecular factors that regulate agerelated changes in cardiac physiology and contribute to the increased cardiovascular risk in. Together, these results identify ageinduced expression of mir34a and inhibition of its target pnuts as a key mechanism that regulates cardiac contractile function during ageing and after acute. Together, these results identify age induced expression of mir 34a and inhibition of its target pnuts as a key mechanism that regulates cardiac contractile function during ageing and after acute. Therapeutic potential of targeting micrornas to regulate cardiac fibrosis. They contain a core of primitive, proliferating cells, and an outer layer of mesenchymalstromal cells and differentiating cells that express cardiomyocyte proteins and connexin 43. In patients with acute hf, only mir499 was significantly elevated 2fold. Noncoding rnas controlling telomere homeostasis in senescence. Overwhelming evidence accumulated since their discovery 2,3 leaves little doubt regarding their importance. Effect of aging and sex on circulating micrornas in humans. Because css contain both primitive cells and committed.
In recent years, significant evidence has emerged that supports the highly dynamic and responsive nature of the cardiac extracellular matrix. Cited2 regulates proliferation and survival in young and. Nuclear receptors nrs are ligandactivated transcription factors that regulate gene transcription by binding to the promoter region or by interacting with other transcription factors. Microrna profiling unveils hyperglycaemic memory in the. Together, these results identify ageinduced expression of mir34a and inhibition of its target pnuts as a key mechanism that regulates cardiac contractile function during. Aug 06, 2010 research highlights microrna 34a mir 34a regulates senescence and cell cycle progression in endothelial cells. Microrna34a induces endothelial progenitor cell senescence. Remarkably, mir34a expression was significantly augmented in. Here we show that mir34a is induced in the ageing heart and that in vivosilencing or gene. Microrna34a regulates cardiac ageing and function nature. Generally, stem cells are classified into adult stem cells, embryonic stem cells escs and induced pluripotent stem cells ipscs. Developing mirna therapeutics for cardiac repair in ischemic. Mirnabased therapies for cardiac regeneration and repair still require validation in models.
Agerelated decay can eventually lead to pathology such as cardiovascular and neurodegenerative diseases, cancer, and diabetes. The aging retinal pigment epithelium and oxidative stress, mediated by reactive oxygen species ros accumulation, have been implicated in the mechanisms of agerelated macular degeneration amd. Here we show that mir34a is induced in the ageing heart and that in vivo silencing or genetic deletion of mir34a. Microrna34a mir34a is originally identified as a tp53targeted mirna that modulates.
Cardiac stem cells cscs exhibit agedependent characteristics. Micrornas mirnas are small noncoding rna transcripts that affect various cellular pathways by serving as regulators of gene expression at the translational and transcriptional level. Jul 17, 2019 cardiac stem cells cscs exhibit agedependent characteristics. However, the number and function of mscs decline during hypoxia and serum deprivation hsd, reducing their ability to contribute to endogenous injury repair. Along similar lines, inhibition of mir34a improved cardiac function after mi in mice, attenuating cardiomyocyte apoptosis and telomere shortening. Human cardiospheres as a source of multipotent stem and. Micrornas mirnas, small noncoding rnas, are implicated as important regulators of vascular function, including endothelial cell differentiation, proliferation, and angiogenesis. Jun 12, 2017 over the last decades, life expectancy has significantly increased although several chronic diseases persist in the population, with aging as the leading risk factor.
The agerelated change in cardiac contractility influences the therapeutic effect and intervention timepoint. Aging is a universal and timedependent biological decline associated with progressive deterioration of cells, tissues, and organs. As mouse models of bleomycininduced pulmonary fibrosis display many of the same phenotypes observed in patients with idiopathic pulmonary fibrosis, they have been used to study various aspects of the disease. Expression of microrna 34a in alzheimers disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Dimmeler discussed the function in the adult of microrna34a, which is induced in the aging heart. Old ocscs showed decreased differentiation and proliferation capacities as compared to young ycscs. Demonstrates that inhibition of mir34 improves cardiac function in mice with preexisting pressure overloadinduced hypertrophy and dysfunction, and can attenuate pathological remodeling after myocardial infarction. Many micrornas are differentially expressed during aging, generating interest in their use as aging. Therapeutic potential of targeting micrornas to regulate. Here we report a regulatory pathway consisting of the rna binding protein rbfox2, a stressinduced microrna mir34a, and the essential ec coupler jph2.
Recent advances in nextgeneration sequencing have reached a stage where it is possible to know from a specific tissue the most abundant transcripts, alternative splicing process. More than 1,000 mirnas are encoded in the human genome. Like most other mirnas, mir34a regulates the expression of multiple genes in different tissues. We speculated that certain mirnas in atrial tissue are related to af, and evaluated the relationship of mirna expression in human atrial tissue in cardiac surgery patients. Apr 04, 2019 cardiac fibrosis, characterized by excessive accumulation of extracellular matrix, abolishes cardiac contractility, impairs cardiac function, and ultimately leads to heart failure. Diabetes induces the activation of pro ageing mir 34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells skip to main content thank you for visiting. For most cardiac ischemia therapies, the therapeutic result in the elderly is not identical to the young.
Integrative annotation of human large intergenic noncoding rnas reveals global properties and specific subclasses. Microrna34a regulates cardiac ageing and function 20 february 20 nature, vol. In the heart tissue, mir34a is induced by aging and contributes to agingrelated decline in cardiac function and cardiac cell death by downregulation of pnuts, which reduces telomere shortening. Here we show that mir 34a is induced in the ageing heart and that in vivo silencing or genetic deletion of mir 34a reduces ageassociated cardiomyocyte cell death. Micrornas mirnas have been reported as potentially being useful biomarkers for various diseases including cancer, diabetes mellitus, heart disease, neurological disease and agerelated diseases. Mir34a was reported to serve an important role in cardiac fibrosis in patients and in mice, and it has been suggested that therapeutic inhibition of members of the mir34 family may attenuate pathological cardiac remodeling and improve cardiac function in patients, as this approach has been proven to be effective in mouse models of cardiac. Noncoding rnas ncrnas are a class of rna molecules that do not encode proteins.
Microrna 34a mir 34a is originally identified as a tp53targeted mirna that modulates. Parallel to its roles in cardiac aging, mir 34a was upregulated in the border zone of infarcted heart, and mir 34a inhibition by ant 34a improved remodeling after mi. Apr 12, 2012 microrna 34a regulates the longevityassociated protein sirt1 in coronary artery disease. May 23, 2018 microrna34a regulates cardiac ageing and function.
Cardiac telomere length was longer in the hhr compared with the control strain at 2 days and 38 wk, but shorter at wk. Mir 34a expression increases during endothelial cell senescence and in older mice. Microrna profiling implicates the insulinlike growth factor. Microrna34a regulates the longevityassociated protein sirt1 in coronary artery disease. Injecting these mirnas into rodent hearts after myocardial infarction mi preserved cardiac function.
In silico analysis and in vitro studies indicate that silent information regulator 1. Nanovectorbased prolyl hydroxylase domain 2 silencing system enhances the efficiency of stem cell transplantation for infarcted myocardium repair. It also regulates normal functions including cell differentiation and organ development. Mesenchymal stem cells confer resistance to doxorubicin. Aging has a remarkable impact on the function of the heart, and is independently associated with. We found that mir34a was highly expressed in aortas isolated from old mice. Aug 29, 20 idiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. They comprise 12% of all genes in worms, flies, and mammals 1, and because each mirna is predicted to regulate hundreds of targets, the majority of protein coding genes is thought to be under. Despite improvements in diagnosis and treatment, many elderlies suffer from cardiovascular problems that are much more frequent in an older, more fragile organism. Cited2 mrna and protein level was downregulated in aging heart tissue and cscs. The expression level of the adapter protein p66shc, a key protein that regulates cellular oxidative stress, is relatively low under normal conditions because of the effects of silent mating type. Here we show that mir 34a is induced in the ageing heart and that in vivosilencing or gene.
Diabetes induces the activation of proageing mir34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells skip to. Microrna34a regulates the longevityassociated protein. A prominent molecular process underlying aging is the progressive shortening of telomeres, the structures that protect the ends of. For example, inhibition of phosphoinositide 3kinase p110. Impaired angiogenesis is a prominent risk factor that contributes to the development of diabetesassociated cardiovascular disease. We propose that altered expression of mirnas in the heart during ageing contributes to the agedependent decline in cardiac function. Severe abdominal aortic calcification aac is associated with higher risk of cardiovascular event and of fragility fracture. Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. Frontiers generation of microrna34 sponges and tough.
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