A long noncoding RNA CHAIR protects the heart from pathological stress

Abstract Mammalian genomes have been found to be extensively transcribed. In addition to classic protein coding genes, a large numbers of long noncoding genes (lncRNAs) have been identified, while their functions, especially in heart diseases, remain to be established. We hypothesized that heart failure progression is controlled by tissue-specific lncRNAs. In the present study, we found that the cardiac-enriched lncRNA 4632428C04Rik, named as cardiomyocyte hypertrophic associated inhibitory RNA (CHAIR), is dynamically regulated during heart development, is expressed at low levels in embryonic hearts and accumulated at high levels in adult hearts. More interestingly, the lncRNA was down-regulated during cardiac hypertrophy and failure both in mice and humans. Importantly, loss of lncRNA CHAIR has no effects on normal hearts, whereas it results in accelerated heart function decline, increased hypertrophy, and exacerbated heart failure in response to stress. In contrast, restoring the expression of lncRNA CHAIR rescued the hearts from hypertrophy and failure. DNMT3A was recruited to CHAIR promoter during heart failure to suppress its expression. Reciprocally, CHAIR interacted with DNMT3A to inhibit its DNA-binding activity. Taken together, our data revealed a new cardioprotective lncRNA that represses heart failure through an epigenetic mechanism.

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Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248417725058 ◽

2017 ◽

Vol 23 (1) ◽

pp. 89-97 ◽

Cited By ~ 1

Author(s):

Monika Skrzypiec-Spring ◽

Katarzyna Haczkiewicz ◽

Agnieszka Sapa ◽

Tomasz Piasecki ◽

Joanna Kwiatkowska ◽

...

Keyword(s):

Heart Failure ◽

Troponin I ◽

Heart Function ◽

Heart Diseases ◽

Acute Myocarditis ◽

Study Groups ◽

Matrix Metalloproteinase 2 ◽

Autoimmune Myocarditis ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

Aims: Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases’ (MMPs) activation have not been elucidated. Methods and Results: Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. Conclusions: The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation.

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Abstract 19292: KLF4 Regulates Mitochondrial Homeostasis in the Heart

Circulation ◽

10.1161/circ.132.suppl_3.19292 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Xudong Liao ◽

Mukesh Jain

Keyword(s):

Heart Failure ◽

Mitochondrial Biogenesis ◽

Transcriptional Control ◽

Heart Function ◽

Heart Diseases ◽

Pressure Overload ◽

Premature Mortality ◽

Mitochondrial Homeostasis ◽

Adult Mice ◽

Mitochondrial Heterogeneity

Mitochondrial homeostasis is critical for heart function and mitochondrial dysfunction contributes to numerous heart diseases such as heart failure. Our previous work indicates that mice with cardiomyocyte-restricted deficiency of KLF4 develop heart failure precipitously in response to pressure-overload but the underlying mechanisms remain unknown. We hypothesized that KLF4 may regulate mitochondrial function in the heart. Here we show that KLF4 governs mitochondrial biogenesis, metabolic function, dynamics and autophagic clearance. Adult mice with cardiac-specific KLF4 deficiency develop cardiac dysfunction with aging or in response to pressure overload characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial heterogeneity and alignment. Studies in mitochondria isolated from KLF4-deficient hearts revealed reduced respiration rate likely due to defects in ETC Complex I. Further, embryonic cardiac KLF4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. Mechanistically, we show that KLF4 binds to, cooperates with, and is requisite for optimal function of the ERR/PGC-1 transcriptional regulatory module on metabolic and mitochondrial targets. Finally, KLF4 also regulates autophagy through transcriptional control of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis.

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Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs

Circulation ◽

10.1161/circulationaha.119.045116 ◽

2020 ◽

Vol 142 (9) ◽

pp. 868-881 ◽

Cited By ~ 2

Author(s):

Andrea Baehr ◽

Kfir Baruch Umansky ◽

Elad Bassat ◽

Victoria Jurisch ◽

Katharina Klett ◽

...

Keyword(s):

Heart Failure ◽

Single Dose ◽

Matrix Protein ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Heart Function ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Extracellular Matrix Protein ◽

Number Of Patients

Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia–reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin’s mechanisms of action. Conclusions: A single dose of agrin is capable of reducing ischemia–reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.

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Long Noncoding RNA SOX2-OT Exacerbates Hypoxia-Induced Cardiomyocytes Injury by Regulating miR-27a-3p/TGFβR1 Axis

Cardiovascular Therapeutics ◽

10.1155/2020/2016259 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Guang Yang ◽

Chunsheng Lin

Keyword(s):

Heart Failure ◽

Cell Apoptosis ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Heart Diseases ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Cellular Processes ◽

Wide Range

Background. Myocardial infarction (MI) was a severe cardiovascular disease resulted from acute, persistent hypoxia, or ischemia condition. Additionally, MI generally led to heart failure, even sudden death. A multitude of research studies proposed that long noncoding RNAs (lncRNAs) frequently participated in the regulation of heart diseases. The specific function and molecular mechanism of SOX2-OT in MI remained unclear. Aim of the Study. The current research was aimed to explore the role of SOX2-OT in MI. Methods. Bioinformatics analysis (DIANA tools and Targetscan) and a wide range of experiments (CCK-8, flow cytometry, RT-qPCR, luciferase reporter, RIP, caspase-3 activity, trans-well, and western blot assays) were adopted to investigate the function and mechanism of SOX2-OT. Results. We discovered that hypoxia treatment decreased cell viability but increased cell apoptosis. Besides, lncRNA SOX2-OT expression was upregulated in hypoxic HCMs. Hereafter, we confirmed that SOX2-OT could negatively regulate miR-27a-3p levels by directly binding with miR-27a-3p, and miR-27a-3p also could negatively regulate SOX2-OT levels. Furthermore, knockdown of SOX2-OT promoted cell proliferation, migration, and invasion, but limited cell apoptosis. However, these effects were reversed by anti-miR-27a-5p. Besides, we verified that miR-27a-3p binding with the 3′UTR of TGFBR1 and SOX2-OT regulated TGFβR1 level by collaborating with miR-27a-3p in HCMs. Eventually, rescue assays validated that the influence of SOX2-OT silence or miR-27a-3p overexpression on cellular processes in cardiomyocytes injury was counteracted by TGFBR1 overexpression. Conclusions. Long noncoding RNA SOX2-OT exacerbated hypoxia-induced cardiomyocytes injury by regulating miR-27a-3p/TGFβR1 axis, which may provide a novel insight for heart failure treatment.

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G9a is transactivated by C/EBPβ to facilitate mitotic clonal expansion during 3T3-L1 preadipocyte differentiation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00608.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. E990-E998 ◽

Cited By ~ 18

Author(s):

Shu-Fen Li ◽

Liang Guo ◽

Shu-Wen Qian ◽

Yuan Liu ◽

You-You Zhang ◽

...

Keyword(s):

Clonal Expansion ◽

Binding Activity ◽

Epigenetic Mechanism ◽

Peroxisome Proliferator ◽

Preadipocyte Differentiation ◽

Peroxisome Proliferator Activated Receptor ◽

Dna Binding Activity ◽

Enhancer Binding Protein ◽

H3k9 Dimethylation ◽

Mitotic Clonal Expansion

In 3T3-L1 preadipocyte differentiation, the CCAAT/enhancer-binding protein-β (C/EBPβ) is an important early transcription factor that activates cell cycle genes during mitotic clonal expansion (MCE), sequentially activating peroxisome proliferator-activated receptor-γ (PPARγ) and C/EBPα during terminal differentiation. Although C/EBPβ acquires its DNA binding activity via dual phosphorylation at about 12–16 h postinduction, the expression of PPARγ and C/EBPα is not induced until 36–72 h. The delayed expression of PPARγ and C/EBPα ensures the progression of MCE, but the mechanism responsible for the delay remains elusive. We provide evidence that G9a, a major euchromatic methyltransferase, is transactivated by C/EBPβ and represses PPARγ and C/EBPα through H3K9 dimethylation of their promoters during MCE. Inhibitor- or siRNA-mediated G9a downregulation modestly enhances PPARγ and C/EBPα expression and adipogenesis in 3T3-L1 preadipocytes. Conversely, forced expression of G9a impairs the accumulation of triglycerides. Thus, this study elucidates an epigenetic mechanism for the delayed expression of PPARγ and C/EBPα.

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Abstract 263: A Decline in Kidney-derived Protein Klotho Contributes to Aging-related Heart Failure

Circulation Research ◽

10.1161/res.119.suppl_1.263 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Zhongjie Sun ◽

Kai Chen

Keyword(s):

Heart Failure ◽

Therapeutic Strategy ◽

Contractile Function ◽

Heart Function ◽

Heart Diseases ◽

Daily Injection ◽

Aged Mice ◽

Adult Mice ◽

Effective Therapeutic Strategy ◽

Klotho Protein

Background & Objective: The heart function declines in the aged population. At age 80 years, LV contractile function is less than half of what it was at age 20 years. Aging is a recognized risk factor for heart diseases. For instance, the prevalence of heart disease increases with age. The mortality from heart diseases is higher in the aged than in the young population. Klotho is a recently discovered anti-aging gene that is primarily expressed in kidneys. The secreted Klotho is released into blood. The objective of this study is to investigate if a decline serum Klotho levels contributes to aging-related heart failure. Method & Results: The results showed that ejection fraction, stroke volume and cardiac output were decreased in aged mice (24 months) vs. the adult mice (10 months), indicating that aging impairs heart function. The serum level of Klotho was decreased significantly in aged mice. Interestingly, daily injection of recombinant Klotho protein rescued the aging-related decline in heart function. Mutation of Klotho gene ( KL -/- ) resulted in heart failure which was associated with a significant increase in serum phosphate levels (hyperphosphatemia). Low phosphate diet delayed but did not prevent the development of heart failure in male KL -/- mice, suggesting that hyperphosphatemia partially contributes to Klotho deficiency-induced heart failure. Unfortunately, low phosphate diet failed to improve heart failure in female KL -/- mice. Interestingly, administration of estrogen decreased hyperphosphatemia and delayed the development of heart failure in KL -/- although it did not prevent Klotho deficiency-induced heart failure. Therefore, Conclusion: Klotho deficiency contributes to aging-related heart failure. Hyperphosphatemia accelerated the development of Klotho deficiency-induced heart failure. Administration of recombinant Klotho protein is an effective therapeutic strategy for heart aging. (supported by NIH R01 HL118558, AG049780, DK093403).

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Abstract 471: Paradigm Shift to Epigenetic Memory for the Pathological Understanding of Chronic Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_304-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Yoshihiro Asano ◽

Seiji Takashima ◽

Yulin Liao ◽

Masafumi Kitakaze

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Transcription Factors ◽

Chronic Heart Failure ◽

Chromatin Structure ◽

Epigenetic Modification ◽

Heart Function ◽

Epigenetic Mechanism ◽

Epigenetic Markers

Background- Epigenetic modification becomes a popular regulatory mechanism of gene expression in development or tumor progression. However its role in cardiovascular diseases has not been elucidated. Since reactivation of cardiac fetal gene expression in chronic heart failure (CHF) is more remarkable than that expected by the increased transcriptional factors, the concept of epigenetic modification may be required for the explanation of such a phenomenon. We tested this idea. Methods- To test the epigenetic potency in cardiomyocytes, we focused on the expression of both BNP and ANP genes. As epigenetic markers, nucleic chromatin structure by electron microscopy and the entire-regional histone modifications were evaluated using our newly developed in vivo chromatin immunoprecipitation (ChIP) assay. Results- In the developmental stage of hearts, we observed a parallel movement of fetal gene expression and epigenetic markers. On the other hand, in the short time stimuli of GPCR agonists in murine cardiomyocytes, fetal gene expression was controlled only by the amount of transcription factors, Gata4 and Nkx2.5, but epigenetic maker was not altered. In contrast, in in vivo murine model of CHF both Gata4 and Nkx2.5 depressed despite elevated expression of both BNP and ANP. Nucleic chromatin structure in failing cardiomyocytes was changed to less condensed forms and increased accumulation of both histone H3K9-acetylation and H3K4-trimethylation was observed across these gene loci. Also in human failing heart, similar changes of nucleic chromatin structure were observed as that in murine CHF model and interestingly these changes was reversed when the heart function was recovered along with proper treatment. Conclusions- We for the first time clarified that both BNP and ANP reactivation mechanisms in chronic heart failure link to the alteration of histone modification by the in vivo ChIP method. Different from acute stimuli, this change was coincided with nucleic chromatin structure and was explicable of paradoxical depression of transcription factors, suggesting epigenetic potency. Epigenetic mechanism may play a pivotal role in the nuclear memory-mediating failing myocardium, raising the hope for a novel pathological understanding for human CHF.

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Regulatory RNAs in Heart Failure

Circulation ◽

10.1161/circulationaha.119.042474 ◽

2020 ◽

Vol 141 (4) ◽

pp. 313-328 ◽

Cited By ~ 16

Author(s):

Clarissa Pedrosa da Costa Gomes ◽

Blanche Schroen ◽

Gabriela M. Kuster ◽

Emma L. Robinson ◽

Kerrie Ford ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Cardiovascular Disease ◽

Noncoding Rna ◽

Regulation Of Gene Expression ◽

Noncoding Rnas ◽

Circular Rnas ◽

Regulatory Rna ◽

Messenger Rnas ◽

Protein Coding

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.

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Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs

10.1101/854372 ◽

2019 ◽

Cited By ~ 1

Author(s):

Andrea Baehr ◽

Kfir Baruch Umansky ◽

Elad Bassat ◽

Katharina Klett ◽

Victoria Jurisch ◽

...

Keyword(s):

Heart Failure ◽

Single Dose ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Heart Function ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Life Quality ◽

Cardiac Regeneration ◽

Adult Mice

AbstractIschemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We have recently reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Here, we tested the therapeutic potential of Agrin in a preclinical porcine model, comprising either 3 or 28 days (d) reperfusion period. We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of rhAgrin resulted in significant improvement in heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiment along with complementary murine MI studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin’s mechanisms of action. We conclude that a single dose of Agrin is capable of reducing ischemia reperfusion injury and improving cardiac function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure.

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