HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m5 C Methylation of Atf7 mRNA.

PIWI-interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis-associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)-mediated 5-methylcytosine (m5 C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes and I/R-injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5 C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA-mediated m5 C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP-DNMT1-ATF7-CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA.

The mitochondrial transmembrane (TMEM) protein family has several essential physiological functions. However, its roles in cardiomyocyte proliferation and cardiac regeneration remain unclear. Here, we detected that TMEM11 inhibits cardiomyocyte proliferation and cardiac regeneration in vitro. TMEM11 deletion enhanced cardiomyocyte proliferation and restored heart function after myocardial injury. In contrast, TMEM11-overexpression inhibited neonatal cardiomyocyte proliferation and regeneration in mouse hearts. TMEM11 directly interacted with METTL1 and enhanced m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. A TMEM11-dependent increase in ATF5 promoted the transcription of Inca1, an inhibitor of cyclin-dependent kinase interacting with cyclin A1, which suppressed cardiomyocyte proliferation. Hence, our findings revealed that TMEM11-mediated m7G methylation is involved in the regulation of cardiomyocyte proliferation, and targeting the TMEM11-METTL1-ATF5-INCA1 axis may serve as a novel therapeutic strategy for promoting cardiac repair and regeneration.

ABRO1 arrests cardiomyocyte proliferation and myocardial repair by suppressing PSPH.

The role of Abraxas 2 (ABRO1 or KIAA0157), a component of the lysine63-linked deubiquitinating system, in the cardiomyocyte proliferation and myocardial regeneration is unknown. Here, we found that ABRO1 regulates cardiomyocyte proliferation and cardiac regeneration in the postnatal heart by targeting METTL3-mediated m6A methylation of Psph mRNA. The deletion of ABRO1 increased cardiomyocyte proliferation in hearts and restored the heart function after myocardial injury. On the contrary, ABRO1 overexpression significantly inhibited the neonatal cardiomyocyte proliferation and cardiac regeneration in mouse hearts. The mechanism by which ABRO1 regulates cardiomyocyte proliferation mainly involved METTL3-mediated Psph mRNA methylation and CDK2 phosphorylation. In the early postnatal period, METTL3-dependent m6A methylation promotes cardiomyocyte proliferation by hypermethylation of Psph mRNA and upregulating PSPH expression. PSPH dephosphorylates cyclin-dependent kinase 2 (CDK2), a positive regulator of cell cycle, at Thr14/Tyr15 and increases its activity. Upregulation of ABRO1 restricts METTL3 activity and halts the cardiomyocyte proliferation in the postnatal hearts. Thus, our study reveals that ABRO1 is an essential contributor in the cell cycle withdrawal and attenuation of proliferative response in the postnatal cardiomyocytes and could act as a potential target to accelerate cardiomyocyte proliferation and cardiac repair in the adult heart.

Human brucellosis and fever of unknown origin.

BACKGROUND: Human brucellosis has become one of the major public health problems in China, and increases atypical manifestations, such as fever of unknown origin (FUO), and misdiagnosis rates has complicated the diagnosis of brucellosis. To date, no relevant study on the relationship between brucellosis and FUO has been conducted. METHODS: We retrospectively reviewed the medical charts of 35 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. The patients were admitted to the Second Affiliated Hospital of Nanchang University between January 01, 2013 and October 31, 2019. Patient data were collected from hospital medical records. RESULTS: The percentage of males was significantly higher than that of female in FUO (78.95% vs. 21.05%, P < 0.05), and 80% of the patients had a clear history of exposure to cattle and sheep. Moreover, 19 (54%) cases were hospitalized with FUO, among which the patients with epidemiological histories were significantly more than those without (P < 0.05). The incidence of toxic hepatitis in FUO patients was higher than that in non-FUO patients (89% vs. 50%, P < 0.05). Meanwhile, the misdiagnosis rate was considerably higher in the FUO group than in the non-FUO group (100% vs. 63%; P < 0.05). CONCLUSION: Brucellosis is predominantly FUO admission in a non-endemic area of China, accompanied by irregular fever and toxic hepatitis. Careful examination of the epidemiological history and timely improvement of blood and bone marrow cultures can facilitate early diagnosis and prevent misdiagnosis.

Sensitive naked-eye detection of telomerase activity based on exponential amplification reaction and lateral flow assay.

Telomerase is a promising diagnostic and prognostic biomarker for cancers. Sensitive, simple, and reliable telomerase activity detection is vital for cancer diagnosis. Herein, we developed an ultrasensitive visualized assay for telomerase activity that combined the exponential amplification reaction (EXPAR) and lateral flow assay for easy and quick signal readout, which we termed as a lateral flow readout-EXPAR (LFR-EXPAR) assay. In the LFR-EXPAR assay, telomerase elongation products initiate the exponential amplification reaction, the generated trigger hybridizes with the reporter to form the recognition site of the nicking enzyme, and the nicking enzyme cuts the reporter strand. The degradation of the reporter can be detected with a universal lateral flow dipstick and read out with the naked eye. After conducting a series of proof-of-concept investigations, the LFR-EXPAR assay was found to achieve a sensitivity comparable to that of a TRAP (telomere repeat amplification protocol) assay. The LFR-EXPAR assay can be used to realize ultrasensitive and point-of-care detection of telomerase without requiring specialized instruments, holding great promise for early cancer diagnosis.

Insights Into Ferroptosis, a Novel Target for the Therapy of Cancer.

Ferroptosis is a new form of programmed cell death (PCD) characterized by an excess iron accumulation and subsequent unbalanced redox states. Ferroptosis is different from the already reported PCD and has unique morphological features and biochemical processes. Ferroptosis was first elaborated by Brent R. Stockwell's lab in 2012, in which small molecules erastin and RSL-3 induce PCD in Ras mutant cell lines. Ferroptosis involves various physiological processes and occurrence of disease and especially shows strong potential in cancer treatment. Development of small molecule compounds based on Stockwell's research was found to kill cancer cells, and some FDA-approved drugs were discovered to result in ferroptosis of cancer cells. Radiotherapy and checkpoint therapy have been widely used as a treatment for many types of cancer. Recently, some papers have reported that chemotherapy, radiotherapy, and checkpoint therapy induce ferroptosis of cancer cells, which provides new strategies for cancer treatment. Nevertheless, the limitless proliferation of tumor cells and the lack of cell death mechanisms are important reasons for drug resistance for tumor therapy. Therefore, we reviewed the molecular mechanism of ferroptosis and sensitivity to ferroptosis of different cancer cells and tumor treatment strategy.

PIWI-Interacting RNA HAAPIR Regulates Cardiomyocyte Death After Myocardial Infarction by Promoting NAT10-Mediated ac4 C Acetylation of Tfec mRNA.

PIWI-interacting RNAs (piRNAs) are abundantly expressed in heart. However, their functions and molecular mechanisms during myocardial infarction remain unknown. Here, a heart-apoptosis-associated piRNA (HAAPIR), which regulates cardiomyocyte apoptosis by targeting N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4 C) acetylation of transcription factor EC (Tfec) mRNA transcript, is identified. HAAPIR deletion attenuates ischemia/reperfusion induced myocardial infarction and ameliorate cardiac function compared to WT mice. Mechanistically, HAAPIR directly interacts with NAT10 and enhances ac4 C acetylation of Tfec mRNA transcript, which increases Tfec expression. TFEC can further upregulate the transcription of BCL2-interacting killer (Bik), a pro-apoptotic factor, which results in the accumulation of Bik and progression of cardiomyocyte apoptosis. The findings reveal that piRNA-mediated ac4 C acetylation mechanism is involved in the regulation of cardiomyocyte apoptosis. HAAPIR-NAT10-TFEC-BIK signaling axis can be potential target for the reduction of myocardial injury caused by cardiomyocyte apoptosis in ischemia heart diseases.

circRNA is a potential target for cardiovascular diseases treatment.

Circular RNAs (circRNAs), a novel class of endogenous noncoding RNA, are characterized by their covalently closed-loop structures without a 5' cap or a 3' poly(A) tail. With the evolution of high-throughput sequencing technology and bioinformatics, an increasing number of circRNAs have been discovered, and their functions were highlighted. Cardiovascular diseases (CVDs) have become the world's leading killers, with serious impacts on human health. Although significant progress has been made in clarifying the development of CVDs from the molecular to the cellular level, CVDs remain one of the leading causes of death in humans. circRNAs mainly function as a "sponge" to absorb microRNAs, which results in the positive control of downstream proteins. They play important regulatory roles in the development of CVDs. This paper reviews current knowledge on the biogenesis, detection and validation, translation, translocation and degradation, and general functions of circRNAs, with a focus on their roles in CVDs.

The circRNA CNEACR regulates necroptosis of cardiomyocytes through Foxa2 suppression.

Circular RNAs (circRNAs) are differentially expressed in various cardiovascular disease including myocardial ischemia-reperfusion (I/R) injury. However, their functional impact on cardiomyocyte cell death, in particular, in necrotic forms of death remains elusive. In this study, we found that the level of mmu_circ_000338, a cardiac- necroptosis-associated circRNA (CNEACR), was reduced in hypoxia-reoxygenation (H/R) exposed cardiomyocytes and I/R-injured mice hearts. The enforced expression of CNEACR attenuated the necrotic form of cardiomyocyte death caused by H/R and suppressed of myocardial necrosis in I/R injured mouse heart, which was accompanied by a marked reduction of myocardial infarction size and improved cardiac function. Mechanistically, CNEACR directly binds to histone deacetylase (HDAC7) in the cytoplasm and interferes its nuclear entry. This leads to attenuation of HDAC7-dependent suppression of forkhead box protein A2 (Foxa2) transcription, which can repress receptor-interacting protein kinase 3 (Ripk3) gene by binding to its promoter region. In addition, CNEACR-mediated upregulation of FOXA2 inhibited RIPK3-dependent necrotic/necroptotic death of cardiomyocytes. Our study reveals that circRNAs such as CNEACR can regulate the cardiomyocyte necroptosis associated activity of HDACs, promotes cell survival and improves cardiac function in I/R-injured heart. Hence, the CNEACR/HDAC7/Foxa2/ RIPK3 axis could be an efficient target for alleviating myocardial damage caused by necroptotic death in ischemia heart diseases.

The piRNA CHAPIR regulates cardiac hypertrophy by controlling METTL3-dependent N6-methyladenosine methylation of Parp10 mRNA.

PIWI-interacting RNAs (piRNAs) are abundantly expressed during cardiac hypertrophy. However, their functions and molecular mechanisms remain unknown. Here, we identified a cardiac-hypertrophy-associated piRNA (CHAPIR) that promotes pathological hypertrophy and cardiac remodelling by targeting METTL3-mediated N6-methyladenosine (m6A) methylation of Parp10 mRNA transcripts. CHAPIR deletion markedly attenuates cardiac hypertrophy and restores heart function, while administration of a CHAPIR mimic enhances the pathological hypertrophic response in pressure-overloaded mice. Mechanistically, CHAPIR-PIWIL4 complexes directly interact with METTL3 and block the m6A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3ß and inhibits its kinase activity, which results in the accumulation of nuclear NFATC4 and the progression of pathological hypertrophy. Hence, our findings reveal that a piRNA-mediated RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy and that the CHAPIR-METTL3-PARP10-NFATC4 signalling axis could be therapeutically targeted for treating pathological hypertrophy and maladaptive cardiac remodelling.

NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression.

Mitochondrial dysfunction is involved in the pathogenesis of various cardiovascular disorders. Although mitochondrial dynamics, including changes in mitochondrial fission and fusion, have been implicated in the development of cardiac hypertrophy, the underlying molecular mechanisms remain mostly unknown. Here, we show that NFATc3, miR-153-3p, and mitofusion-1 (Mfn1) constitute a signaling axis that mediates mitochondrial fragmentation and cardiomyocyte hypertrophy. Methods: Isoprenaline (ISO) was used to stimulate the hypertrophic response and mitochondrial fragmentation in cultured cardiomyocytes and in vivo. We performed immunoblotting, immunofluorescence, and quantitative real-time PCR to validate the function of Mfn1 in cardiomyocyte hypertrophy. Bioinformatic analyses, a luciferase reporter assay, and gain- and loss-of-function studies were used to demonstrate the biological function of miR-153-3p, which regulates mitochondrial fragmentation and hypertrophy by targeting Mfn1. Moreover, ChIP-qPCR and a luciferase reporter assay were performed to identify transcription factor NFATc3 as an upstream regulator to control the expression of miR-153-3p. Results: Our results show that ISO promoted mitochondrial fission and enhanced the expression of miR-153-3p in cardiomyocytes. Knockdown of miR-153-3p attenuated ISO-induced mitochondrial fission and hypertrophy in cultured primary cardiomyocytes. miR-153-3p suppression inhibited mitochondrial fragmentation in ISO-induced cardiac hypertrophy in a mouse model. We identified direct targeting of Mfn1, a key protein of the mitochondrial fusion process, by miR-153-3p. Also, miR-153-3p promoted ISO-induced mitochondrial fission by suppressing the translation of Mfn1. We further found that NFATc3 activated miR-153-3p expression. Knockdown of NFATc3 inhibited miR-153-3p expression and blocked mitochondrial fission and hypertrophic response in cardiomyocytes. Conclusions: Our data revealed a novel signaling pathway, involving NFATc3, miR-153-3p, and Mfn1, which could be a therapeutic target for the prevention and treatment of cardiac hypertrophy.

Long Noncoding RNA CPR (Cardiomyocyte Proliferation Regulator) Regulates Cardiomyocyte Proliferation and Cardiac Repair.

BACKGROUND: The adult mammalian cardiomyocytes lose their proliferative capacity, which is responsible for cardiac dysfunction and heart failure following injury. The molecular mechanisms underlying the attenuation of adult cardiomyocyte proliferation remain largely unknown. Because long noncoding RNAs (lncRNAs) have a critical role in the development of cardiovascular problems, we investigated whether lncRNAs have any role in the regulation of cardiomyocyte proliferation and cardiac repair. METHODS: Using bioinformatics and initial analysis, we identified an lncRNA, named CPR (cardiomyocyte proliferation regulator), that has a potential regulatory role in cardiomyocyte proliferation. For in vivo experiments, we generated CPR knockout and cardiac-specific CPR-overexpressing mice. In isolated cardiomyocytes, we used adenovirus for silencing (CPR-small interfering RNA) or overexpressing CPR. To investigate the mechanisms of CPR function in cardiomyocyte proliferation, we performed various analyses including quantitative reverse transcription-polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), transcriptome analyses (microarray assay), RNA pull-down assay, and chromatin immunoprecipitation assay. RESULTS: CPR level is comparatively higher in the adult heart than in the fetal stage. The silencing of CPR significantly increased cardiomyocyte proliferation in postnatal and adult hearts. Moreover, CPR deletion restored the heart function after myocardial injury, which was evident from increased cardiomyocyte proliferation, improvement of myocardial function, and reduced scar formation. In contrast, the neonatal cardiomyocyte proliferation and cardiac regeneration were remarkably suppressed in CPR-overexpressing mice or adeno-associated virus serotype 9-CPR-overexpressing heart. These results indicate that CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration. Next, we found that CPR targets minichromosome maintenance 3, an initiator of DNA replication and cell cycle progression, to suppress cardiomyocyte proliferation. CPR silenced minichromosome maintenance 3 expression through directly interacting and recruiting DNMT3A to its promoter cysteine-phosphate-guanine sites, as evident from decreased minichromosome maintenance 3 promoter methylation and increased minichromosome maintenance 3 expression in CPR knocked-down cardiomyocytes and CPR knockout mouse heart. These results were confirmed in CPR-overexpressing cardiomyocytes and CPR-overexpressing mouse heart. CONCLUSIONS: Together, our findings identified that CPR is a suppressor of cardiomyocyte proliferation and indicated that lncRNAs take part in the regulation of cardiomyocyte proliferation and cardiac repair. Our study provides an lncRNA-based therapeutic strategy for effective cardiac repair and regeneration.

The circular RNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway.

Dysregulated autophagy is associated with many pathological disorders such as cardiovascular diseases. Emerging evidence has suggested that circular RNAs (circRNAs) have important roles in some biological processes. However, it remains unclear whether circRNAs participate in the regulation of autophagy. Here we report that a circRNA, termed autophagy-related circular RNA (ACR), represses autophagy and myocardial infarction by targeting Pink1-mediated phosphorylation of FAM65B. ACR attenuates autophagy and cell death in cardiomyocytes. Moreover, ACR protects the heart from ischemia/reperfusion (I/R) injury and reduces myocardial infarct sizes. We identify Pink1 as an ACR target to mediate the function of ACR in cardiomyocyte autophagy. ACR activates Pink1 expression through directly binding to Dnmt3B and blocking Dnmt3B-mediated DNA methylation of Pink1 promoter. Pink1 suppresses autophagy and Pink1 transgenic mice show reduced myocardial infarction sizes. Further, we find that FAM65B is a downstream target of Pink1 and Pink1 phosphorylates FAM65B at serine 46. Phosphorylated FAM65B inhibits autophagy and cell death in the heart. Our findings reveal a novel role for the circRNA in regulating autophagy and ACR-Pink1-FAM65B axis as a regulator of autophagy in the heart will be potential therapeutic targets in treatment of cardiovascular diseases.

LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription.

Increasing evidence suggests that long noncoding RNAs (lncRNAs) play crucial roles in various biological processes. However, little is known about the effects of lncRNAs on autophagy. Here we report that a lncRNA, termed cardiac autophagy inhibitory factor (CAIF), suppresses cardiac autophagy and attenuates myocardial infarction by targeting p53-mediated myocardin transcription. Myocardin expression is upregulated upon H2O2 and ischemia/reperfusion, and knockdown of myocardin inhibits autophagy and attenuates myocardial infarction. p53 regulates cardiomyocytes autophagy and myocardial ischemia/reperfusion injury by regulating myocardin expression. CAIF directly binds to p53 protein and blocks p53-mediated myocardin transcription, which results in the decrease of myocardin expression. Collectively, our data reveal a novel CAIF-p53-myocardin axis as a critical regulator in cardiomyocyte autophagy, which will be potential therapeutic targets in treatment of defective autophagy-associated cardiovascular diseases.

PIWI family emerging as a decisive factor of cell fate: An overview.

PIWI proteins and piRNAs primarily functions as a safeguard of germline cells by activating epigenetic regulations, silencing transposons and maintaining chromatin structure. Increasing evidences reveal that PIWI proteins and piRNAs have broader functions in many vital biological processes including cell proliferation, differentiation and survival. They have been recognized as a crucial factor in the cellular events due their role in controlling mRNA expression, turnover and translation. PIWIs, with or without its partner non-coding RNA (piRNA), govern the expression and activity of many transcription factors and signaling molecules by mastering their expression and/or post-translational modifications by directly interacting with them. In this review, we focus on the functional role of PIWI family of proteins and piRNA in physiological and pathological conditions. We compile the current knowledge about the impact of alterations of PIWI and/or piRNA on expression and activities of signaling mediators and transcriptional networks associated with cell differentiation, proliferation and survival.

Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression.

Circular RNAs (circRNAs) have important roles in several cellular processes. No study has established the pathophysiological role for circRNAs in the heart. Here, we show that a circRNA (mitochondrial fission and apoptosis-related circRNA (MFACR)) regulates mitochondrial fission and apoptosis in the heart by directly targeting and downregulating miR-652-3p; this in turn blocks mitochondrial fission and cardiomyocyte cell death by suppressing MTP18 translation. MTP18 deficiency reduces mitochondrial fission and suppresses cardiomyocyte apoptosis and MI. miR-652-3p directly downregulates MTP18 and attenuates mitochondrial fission, cardiomyocyte apoptosis, and MI in vitro and in vivo. MFACR directly sequesters miR-652-3p in the cytoplasm and inhibits its activity. MFACR knockdown in cardiomyocytes and mice attenuates mitochondrial fission and MI. Our results reveal a crucial role for circRNA in regulating mitochondrial dynamics and apoptosis in the heart; as such, circRNAs may serve as a potential therapeutic avenue for cardiovascular diseases.

A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223.

AIMS: Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown. METHODS AND RESULTS: Here we show that a circular RNA (circRNA), which we term heart-related circRNA (HRCR), acts as an endogenous miR-223 sponge to inhibit cardiac hypertrophy and heart failure. miR-223 transgenic mice developed cardiac hypertrophy and heart failure, whereas miR-223-deficient mice were protected from hypertrophic stimuli, indicating that miR-223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR-223 downstream target to mediate the function of miR-223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR-223 sponge to sequester and inhibit miR-223 activity, which resulted in the increase of ARC expression. Heart-related circRNA directly bound to miR-223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses. CONCLUSIONS: These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

MicroRNA-2861 regulates programmed necrosis in cardiomyocyte by impairing adenine nucleotide translocase 1 expression.

Necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. MicroRNAs (miRNAs) have emerged as key gene regulators in many diseases. However, how miRNAs contribute to programmed necrosis is poorly defined. Here we report that miR-2861 and adenine nucleotide translocase 1 (ANT1) constitute an axis that regulates necrotic cell death in the heart. Our results show that ANT1 inhibits H2O2-induced cardiomyocytes necrosis. ANT1 also antagonizes myocardial necrosis in a mouse ischemia/reperfusion (I/R) model. We further demonstrate that miR-2861 directly binds to the coding sequence of ANT1 and suppresses the expression of ANT1 mRNA and protein. MiR-2861 induces necrotic cell death. In contrast, knockdown of miR-2861 attenuates H2O2-induced necrosis in cardiomyocytes. Also, miR-2861 knockdown protects heart from I/R injury and necrotic cell death in vivo. MiR-2861 regulates necrosis and myocardial infarction through targeting ANT1. Collectively, these data identify miR-2861 and ANT1 as two novel regulators of cardiomyocyte necrosis and myocardial infarction, and suggest potential therapeutic targets in treatment of cardiac diseases.

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1.

Mitochondrial fragmentation plays an important role in the progression of cardiac diseases, such as myocardial infarction and heart failure. Mitochondrial network is controlled by many factors in different cell types. Here we show that the interplay between E2F1, miR-421 and Pink1 regulates mitochondrial morphology and cardiomyocyte cell death. Pink1 reduces mitochondrial fragmentation and protects cardiomyocyte from apoptosis. On the other hand, miR-421 promotes cardiomyocyte mitochondrial fragmentation, apoptosis and myocardial infarction by suppressing Pink1 translation. Finally, we show that transcription factor E2F1 activates miR-421 expression. Knocking down E2F1 suppresses mitochondrial fragmentation, apoptosis and myocardial infarction by affecting miR-421 levels. Collectively, these data identify the E2F1/miR-421/Pink axis as a regulator of mitochondrial fragmentation and cardiomyocyte apoptosis, and suggest potential therapeutic targets in treatment of cardiac diseases.