A role is demonstrated for mir 34a, a microrna that is upregulated in the ageing heart. Our in vitro and in vivo results indicated that after doxo exposure the levels of mir 34a are enhanced in cardiac cells, including cardiac progenitor cells cpcs. Expression of microrna 34a in alzheimers disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. 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.
To understand the process leading to ageassociated alterations is, therefore, of the highest relevance for the development of new treatments. Microrna 34a regulates the longevityassociated protein sirt1 in coronary artery disease. Microribonucleic acids mirnas are in the spotlight as posttranscriptional regulators of gene expression. Alcendor rr, gao s, zhai p, zablocki d, holle e, yu x, et al sirt1 regulates aging and resistance to oxidative stress in the heart. Apr 12, 2018 atrial fibrillation af has a high prevalence and recurrence rate, and is associated with substantial mortality. 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. Microrna34a regulates doxorubicininduced cardiotoxicity. 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. Endothelial senescence is thought to play a role in cad coronary artery disease. Microrna34a regulates cardiac ageing and function 20 february 20 nature, vol.
Expression of microrna34a in alzheimers disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Myocardial infarctioninduced micrornaenriched exosomes. Aging has a remarkable impact on the function of the heart, and is independently associated with. Diabetes induces the activation of proageing mir34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells. Mir 34a has a role in cardiac dysfunction and ageing and is involved in several cellular processes associated with doxo cardiotoxicity. On the basis of previous data showing that mir34a regulates cell senescence, cui and colleagues decided to demonstrate the putative prosenescent activity of mir34a in lung fibroblasts. Igf1 deficiency resists cardiac hypertrophy and myocardial contractile dysfunction role of microrna 1 and microrna 3a echocardiographic evaluation histopathological analysis. Pdf microrna34a regulates cardiac ageing and function.
In addition, several studies have highlighted mir 34a as an important mediator of ageing related cardiac. Frontiers microrna in cardiovascular aging and agerelated. Microrna5a regulates sodiumcalcium exchanger gene expression and cardiac electrical activity eric duong, bsc, jiening xiao, phd, xiao yan qi, phd, stanley nattel, md, fhrs from the department of pharmacology and therapeutics, mcgill university, montreal, canada. They demonstrated that the transfection of these cells with mir34a mimetic induces cellular senescence, as revealed by elevated sa. Mir34a has a role in cardiac dysfunction and ageing and is involved in several cellular processes associated with doxo cardiotoxicity. Suppression of mir34a expression in the myocardium protects. Microrna profiling implicates the insulinlike growth. 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. Seminal work has recently demonstrated that mir 34a is induced in the ageing heart and in vivo silencing or genetic deletion of mir 34a reduces ageassociated cardiomyocyte cell death.
Pdf microrna34a regulates cardiac aging and function. 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. In the long term, agerelated cardiovascular diseases. A the expression of mir34a in the vitreous humor of the three groups of patients was increased. In the present study, we investigated whether sirt1related mirs, including mir9, mir34a, mir2, mir181a, mir195, mir199a, mir199b and mir204. We propose that altered expression of mirnas in the heart during ageing contributes to the age dependent decline. While the etiology of ipf is unknown, many of the characteristics of this disease are mimicked by. Many micrornas are differentially expressed during aging, generating interest in their use as aging. Jul 11, 2019 micrornas mirnas are short, noncoding rnas that posttranscriptionally repress translation or induce mrna degradation of target transcripts through sequencespecific binding. Micrornas mirnas, small noncoding rnas, are implicated as important regulators of vascular function, including endothelial cell differentiation, proliferation, and angiogenesis. Despite improvements in diagnosis and treatment, many elderlies suffer from cardiovascular problems that are much more frequent in an older, more fragile organism. Microrna34a plays a key role in cardiac repair and. Micrornas in cardiovascular ageing the physiological society. The p53mir34 axis in development and disease oxford.
It also regulates normal functions including cell differentiation and organ development. However, the number and function of mscs decline during hypoxia and serum deprivation hsd, reducing their ability to contribute to endogenous injury repair. In the vasculature, sirt1 also regulates endothelial cell function through its action as a deacetylase. 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. 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. Microrna 34a mir 34a is originally identified as a tp53targeted mirna that modulates. Impact of dietary interventions on noncoding rna networks and. Micrornas as modulators of longevity and the aging process.
Microrna34a regulates cardiac ageing and function pubmed. 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. Microrna 34a regulates cardiac ageing and function. It is well known that microrna mir34a serves a role in cardiac dysfunction. Regulatory mechanisms of mitochondrial function and cardiac aging. These findings support our idea that mir34a regulates senescence in endothelial cells. Mar 07, 20 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 myocardial infarction, by inducing dna damage responses and telomere attrition. Diabetes induces the activation of proageing mir34a in the. In the present study, we investigated whether sirt1related mirs, including mir9, mir 34a, mir2, mir181a, mir195, mir199a, mir199b and mir204. Microrna profiling unveils hyperglycaemic memory in the. Microrna34a regulation of endothelial senescence sciencedirect. 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. Microrna34a regulates the longevityassociated protein sirt1.
Mir208 is also highly enriched in cardiomyocytes, and regulates the balance between the. Aug 06, 2010 these findings support our idea that mir 34a regulates senescence in endothelial cells. Nuclear receptors nrs are ligandactivated transcription factors that regulate gene transcription by binding to the promoter region or by interacting with other transcription factors. American journal of respiratory cell and molecular biology. This trend is particularly evident in western countries, where healthier living conditions and better cures are available. Developing mirna therapeutics for cardiac repair in. Aug 01, 20 microrna34a regulates cardiac ageing and function. In silico analysis and in vitro studies indicate that silent information regulator 1. In the long term, agerelated cardiovascular diseases cvds. Our in vitro and in vivo results indicated that after doxo exposure the levels of mir34a are enhanced in cardiac cells, including cardiac progenitor cells cpcs. Microrna34a mir34a is originally identified as a tp53targeted mirna that modulates.
Over the last decades, life expectancy has significantly increased although several chronic diseases persist in the population, with aging as the leading risk factor. Recent statistics indicate that the human population is ageing rapidly. Impaired angiogenesis is a prominent risk factor that contributes to the development of diabetesassociated cardiovascular disease. Microrna34a regulates the longevityassociated protein. Micrornas mirnas are short, noncoding rnas that posttranscriptionally repress translation or induce mrna degradation of target transcripts through sequencespecific binding. Ageing affects cardiac function in multiple manners. Regulation of microrna expression and function by nuclear. Microrna34a regulates doxorubicininduced cardiotoxicity in. May 23, 2018 interestingly, a recent publication found a new mechanism leading to reduced na levels in tissue during ageing. Noncoding rnas in cardiac aging fulltext cellular physiology. Mesenchymal stem cell mscbased therapies have had positive outcomes both in animal models of cardiovascular diseases and in clinical patients. Boon, kazuma iekushi, stefanie lechner, timon seeger, ariane fischer, susanne heydt, david kaluza, karine treguer, guillaume carmona, angelika bonauer.
Idiopathic pulmonary fibrosis ipf is a progressive disease of the lung interstitium characterized by deposition of extracellular matrix, inflammatory cell infiltration, and fibroblast recruitment and hyperplasia which leads to impaired lung function and ultimately, respiratory failure 1, 2. 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. Research paper microrna34a regulates doxorubicininduced. Aging attenuates cardiac contractility and affects.
Molecular interplay between microrna34a and sirtuin1 in. Furthermore, the role of mir34a in regulating endogenous cardiac regeneration in. In silico analysis and in vitro studies indicate that silent information. Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction.
Diabetes induces the activation of pro ageing mir 34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells. Microrna34a regulates cardiac aging and function article pdf available in nature 4957439. Atrial fibrillation af has a high prevalence and recurrence rate, and is associated with substantial mortality. Microrna34a regulates cardiac ageing and function nasaads. 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. Pdf oxidative stress and epigenetic regulation in ageing.
The insulinlike growth factor1 pathway is an important contributor to cardiac hypertrophy and arrhythmias, and increasing mir1 levels seems to improve cardiac function. This includes the potential of mirnas as therapeutic targets in cardiac and vascular. Frontiers involvement of microrna34a in agerelated. 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. Roles of microrna34a targeting sirt1 in mesenchymal stem. Sirt1, a class iii histone deacetylase, has been implicated in the regulation of cellular metabolism, senescence, and longevity. Camell and colleagues 8 reported that the wellknown loss of the ability to burn fat in the senescent fat tissue can be explained by a gain of function of the macrophages within the adipose tissue atm. Nanovectorbased prolyl hydroxylase domain 2 silencing system enhances the efficiency of stem cell transplantation for infarcted myocardium repair. Micrornas in cardiovascular ageing seeger 2016 the. Micrornas mirnas have emerged as crucial regulators of cardiovascular function and some mirnas have key roles in ageing. A role is demonstrated for mir34a, a microrna that is upregulated in the ageing heart. Mar 21, 2017 through liver rna sequencing and microrna sequencing in mice across multiple energy intake and expenditure interventions, green et al. Noncoding rnas ncrnas are a class of rna molecules that do not encode proteins. Botella lm, sanchezelsner t, sanzrodriguez f, kojima s, shimada j, guerreroesteo m, et al.
We propose that altered expression of mirnas in the heart during ageing contributes to the age dependent decline in cardiac function. Frontiers microrna in cardiovascular aging and age. Sirt1 is a bona fide target of mir34a to regulate cell apoptosis 109. Microrna34a regulates the longevityassociated protein sirt1 in coronary artery disease. However, its underlying mechanisms are not thoroughly understood.
Met, cyclin d1 and cdk6, because they have been reported to be crucial mediators in liver. Interestingly, a recent publication found a new mechanism leading to reduced na levels in tissue during ageing. Microrna34a regulates cardiac ageing and function nature. Mesenchymal stem cells confer resistance to doxorubicininduced. Through liver rna sequencing and microrna sequencing in mice across multiple energy intake and expenditure interventions, green et al. More than 1,000 mirnas are encoded in the human genome. Ageing is one of the most complex processes in nature. Sirt1 was negatively regulated by mir34a and the expression of down stream genes, such. Cardiac fibrosis is increasingly recognized as a common final pathway in advanced heart diseases. Impact of dietary interventions on noncoding rna networks. Igf1 deficiency resists cardiac hypertrophy and myocardial contractile dysfunction role of microrna1 and microrna3a echocardiographic evaluation histopathological analysis. Microrna34a regulates doxorubicininduced cardiotoxicity in rat elena piegari 1, rosa russo, donato cappetta1. Increasing attention has been paid to the roles of micrornas mirs in the pathogenesis of cardiovascular disease, including mir.
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