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.

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.

Objective. To estimate the prevalence of radiographic and symptomatic knee osteoarthritis (OA) in a remote rural region of northern China, and compare them with those reported in Beijing and with data from the Framingham (Massachusetts) cohort. Methods. A population-based cross-sectional survey was conducted among 1,030 residents of Wuchuan County, Inner Mongolia, age >50 years. Survey participants, mostly farmers reporting heavy physical occupational activity, completed an interviewer-based questionnaire, and bilateral weight-bearing posteroanterior semiflexed knee radiographs were obtained. Results. Whereas the overall prevalence of radiographic knee OA was similar to that demonstrated in the Beijing OA study, men in Wuchuan had approximately double the prevalence of severe radiographic knee OA (prevalence ratio [PR] 2.5, 95% confidence interval [95% CI] 1.6 -3.8) and symptomatic knee OA (PR 1.9, 95% CI 1.3-2.9). Women in Wuchuan also had a higher prevalence of both severe radiographic (PR 1.4, 95% CI 1.0 -2.0) and symptomatic knee OA (PR 1.6, 95% CI 1.2-2.1) compared with their Beijing counterparts. The prevalence of bilateral OA and lateral compartment disease were 2-3 times higher in both Chinese cohorts compared with estimates from the Framingham OA study. Conclusion. The prevalence of symptomatic knee OA in rural areas of China is much higher than reported from urban regions of China or in the Framingham cohort. The higher representation of bilateral and lateral compartment disease in China suggests a unique phenotype to OA. These findings will be useful for guiding the distribution of future health care resources and preventive strategies.

I.

Organismal aging is driven by interconnected molecular changes encompassing internal and extracellular factors. Combinational analysis of high-throughput ‘multi-omics’ datasets (gathering information from genomics, epigenomics, transcriptomics, proteomics, metabolomics and pharmacogenomics), at either populational or single-cell levels, can provide a multi-dimensional, integrated profile of the heterogeneous aging process with unprecedented throughput and detail. These new strategies allow for the exploration of the molecular profile and regulatory status of gene expression during aging, and in turn, facilitate the development of new aging interventions. With a continually growing volume of valuable aging-related data, it is necessary to establish an open and integrated database to support a wide spectrum of aging research. The Aging Atlas database aims to provide a wide range of life science researchers with valuable resources that allow access to a large-scale of gene expression and regulation datasets created by various high-throughput omics technologies. The current implementation includes five modules: transcriptomics (RNA-seq), single-cell transcriptomics (scRNA-seq), epigenomics (ChIP-seq), proteomics (protein–protein interaction), and pharmacogenomics (geroprotective compounds). Aging Atlas provides user-friendly functionalities to explore age-related changes in gene expression, as well as raw data download services. Aging Atlas is freely available at https://bigd.big.ac.cn/aging/index.

Knee SxOA was associated with an increased risk of all-cause mortality among the residents in the rural areas of China.

The objective of this study is to investigate the association between osteoarthritis (OA) and all-cause mortality in worldwide populations and to develop recommendations according to GRADE evidence levels. Literature search through Nov 2015 was performed using the electronic databases (including MEDLINE, EMBASE, EBSCO and Cochrane library). The prospective cohort trials that investigated the association between the symptomatic OA (SxOA) or radiological OA (ROA) and all-cause mortality were identified. Hazard ratios (HR) of all-cause mortality in patients with RxOA or ROA were pooled respectively. The evidence quality was evaluated using the GRADE system, while the recommendations were taken according to the quality. Nine of the published literature met the eligible criteria. Meta-analysis revealed that there was no significant difference in the association between SxOA and all-cause mortality (HR = 0.91, 95% CI: 0.68–1.23) and between ROA and all-cause mortality (HR = 1.13, 95% CI: 0.95–1.35). The overall GARDE evidence quality was very low, which will lower our confidence in taking recommendations. To summarize, there was no reliable and confident evidence existed currently in respect of the association between OA and all-cause mortality. Due to the very low level of evidence quality currently, high-quality studies are still required.

Mitochondrial dysfunction plays a major role in the pathogenesis of cardiovascular diseases. MicroRNAs (miRNAs) are small RNAs that act as negative regulators of gene expression, but how miRNAs affect mitochondrial function in the heart is unclear. Using a miRNA microarray assay, we found that miR-762 predominantly translocated in the mitochondria and was significantly upregulated upon anoxia/reoxygenation (A/R) treatment. Knockdown of endogenous miR-762 significantly attenuated the decrease in intracellular ATP levels, the increase in ROS levels, the decrease in mitochondrial complex I enzyme activity and the increase in apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. In addition, knockdown of miR-762 ameliorated myocardial ischemia/reperfusion (I/R) injury in mice. Mechanistically, we showed that enforced expression of miR-762 dramatically decreased the protein levels of endogenous NADH dehydrogenase subunit 2 (ND2) but had no effect on the transcript levels of ND2. The luciferase reporter assay showed that miR-762 bound to the coding sequence of ND2. In addition, knockdown of endogenous ND2 significantly decreased intracellular ATP levels, increased ROS levels, reduced mitochondrial complex I enzyme activity and increased apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. Furthermore, we found that the inhibitory effect of miR-762 downregulation was attenuated by ND2 knockdown. Thus, our findings suggest that miR-762 participates in the regulation of mitochondrial function and cardiomyocyte apoptosis by ND2, a core assembly subunit of mitochondrial complex I. Our results revealed that mitochondrial miR-762, as a new player in mitochondrial dysfunction, may provide a new therapeutic target for myocardial infarction.