Histone modification landscape and the key significance of H3K27me3 in myocardial ischaemia/reperfusion injury.

Histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury. However, a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established. Here, we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury. Disease-specific histone mark alterations were mainly found in H3K27me3-, H3K27ac-, and H3K4me1-marked regions 24 and 48 h after I/R. Genes differentially modified by H3K27ac, H3K4me1 and H3K27me3 were involved in immune response, heart conduction or contraction, cytoskeleton, and angiogenesis. H3K27me3 and its methyltransferase polycomb repressor complex 2 (PRC2) were upregulated in myocardial tissues after I/R. Upon selective inhibition of EZH2 (the catalytic core of PRC2), the mice manifest improved cardiac function, enhanced angiogenesis, and reduced fibrosis. Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro. This study delineates a landscape of histone modifications in myocardial I/R injury, and identifies H3K27me3 as a key epigenetic modifier in I/R process. The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention.

Stimuli-Triggered Multishape, Multimode, and Multistep Deformations Designed by Microfluidic 3D Droplet Printing.

Elastomers generally possess low Young's modulus and high failure strain, which are widely used in soft robots and intelligent actuators. However, elastomers generally lack diverse functionalities, such as stimulated shape morphing, and a general strategy to implement these functionalities into elastomers is still challenging. Here, a microfluidic 3D droplet printing platform is developed to design composite elastomers architected with arrays of functional droplets. Functional droplets with controlled size, composition, position, and pattern are designed and implemented in the composite elastomers, imparting functional performances to the systems. The composited elastomers are sensitive to stimuli, such as solvent, temperature, and light, and are able to demonstrate multishape (bow- and S-shaped), multimode (gradual and sudden), and multistep (one- and two-step) deformations. Based on the unique properties of droplet-embedded composite elastomers, a variety of stimuli-responsive systems are developed, including designable numbers, biomimetic flowers, and soft robots, and a series of functional performances are achieved, presenting a facile platform to impart diverse functionalities into composite elastomers by microfluidic 3D droplet printing.

PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis.

Sepsis is a life-threatening syndrome with multi-organ dysfunction in critical care medicine. With the occurrence of sepsis-induced cardiomyopathy (SIC), characterized by reduced ventricular contractility, the mortality of sepsis is boosted to 70-90%. Pyruvate kinase M2 (PKM2) functions in a variety of biological processes and diseases other than glycolysis, and has been documented as a cardioprotective factor in several heart diseases. It is currently unknown whether PKM2 influences the development of SIC. Here, we found that PKM2 was upregulated in cardiomyocytes treated with LPS both in vitro and in vivo. Pkm2 inhibition exacerbated the LPS-induced cardiac damage to neonatal rat cardiomyocytes (NRCMs). Furthermore, cardiomyocytes lacking PKM2 aggravated LPS-induced cardiomyopathy, including myocardial damage and impaired contractility, whereas PKM2 overexpression and activation mitigated SIC. Mechanism investigation revealed that PKM2 interacted with sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), a key regulator of the excitation-contraction coupling, to maintain calcium homeostasis, and PKM2 deficiency exacerbated LPS-induced cardiac systolic dysfunction by impairing SERCA2a expression. In conclusion, these findings highlight that PKM2 plays an essential role in gram-negative sepsis-induced cardiomyopathy, which provides an attractive target for the prevention and treatment of septic cardiomyopathy.

Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.

Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate-limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte-specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α-MHC (myosin heavy chain)-Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno-associated virus serotype 9 system. The results showed that cardiomyocyte-specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction-induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)-MAPK (mitogen-activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload-induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.

SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation.

Anthracyclines including doxorubicin (DOX) are still the most widely used and efficacious antitumor drugs, although their cardiotoxicity is a significant cause of heart failure. Despite considerable efforts being made to minimize anthracycline-induced cardiac adverse effects, little progress has been achieved. In this study, we aimed to explore the role and underlying mechanism of SNX17 in DOX-induced cardiotoxicity. We found that SNX17 was downregulated in cardiomyocytes treated with DOX both in vitro and in vivo. DOX treatment combined with SNX17 interference worsened the damage to neonatal rat ventricular myocytes (NRVMs). Furthermore, the rats with SNX17 deficiency manifested increased susceptibility to DOX-induced cardiotoxicity (myocardial damage and fibrosis, impaired contractility and cardiac death). Mechanistic investigation revealed that SNX17 interacted with leiomodin-2 (LMOD2), a key regulator of the thin filament length in muscles, via its C-TERM domain and SNX17 deficiency exacerbated DOX-induced cardiac systolic dysfunction by promoting aberrant LMOD2 degradation through lysosomal pathway. In conclusion, these findings highlight that SNX17 plays a protective role in DOX-induced cardiotoxicity, which provides an attractive target for the prevention and treatment of anthracycline induced cardiotoxicity.

The Regulatory Role of Histone Modification on Gene Expression in the Early Stage of Myocardial Infarction.

Myocardial infarction (MI) is a fatal heart disease with high morbidity and mortality. Various studies have demonstrated that a series of relatively specific biological events occur within 24 h of MI. However, the roles of histone modifications in this pathological process are still poorly understood. To investigate the regulation of histone modifications on gene expression in early MI, we performed RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) on myocardial tissues 24 h after the onset of MI. The genome-wide profiles of five histone marks (H3K27ac, H3K9ac, H3K4me3, H3K9me3, and H3K27me3) were explored through ChIP-seq. RNA-seq identified 1,032 differentially expressed genes (DEGs) between the MI and sham groups. ChIP-seq analysis found that 195 upregulated DEGs were modified by change of at least one of the three active histone marks (H3K27ac, H3K9ac, and H3K4me3), and the biological processes and pathways analysis showed that these DEGs were significantly enriched in cardiomyocyte differentiation and development, inflammation, angiogenesis, and metabolism. In the transcriptional regulatory network, Ets1, Etv1, and Etv2 were predicted to be involved in gene expression regulation. In addition, by integrating super-enhancers (SEs) with RNA-seq data, 76 DEGs were associated with H3K27ac-enriched SEs in the MI group, and the functions of these SE-associated DEGs were mainly related to angiogenesis. Our results suggest that histone modifications may play important roles in the regulation of gene expression in the early stage of MI, and the early angiogenesis response may be initiated by SEs.

Association of ambient air pollutants and birth weight in Ningbo, 2015-2017.

Previous studies have suggested a change of birth weight linked with elevated ambient air pollutant concentrations during the pregnancy. However, investigations of the influence of higher pollutant levels on birth weight change are limited. The goal of this study is to evaluate whether the air pollution of Ningbo is associated with birth weight, and which trimester could be a window period for maternal exposure to air pollution. A total of 170,008 live births were selected in the Ningbo city of Zhejiang, China, from 2015 to 2017. We estimated the association between the decreased birth weight and the increased air pollutant concentrations in the three trimesters and full gestation. The effects of interaction among pollutants were identified using a co-pollutant adjustment model. An interquartile range increases in PM2.5 (10.55 µg/m3), SO2(4.6 µg/m3), CO (125.59 µg/m3), and O3 (14.54 µg/m3) concentrations during the entire gestation were associated with 3.65 g (95% confidence interval: -6.02 g, -1.29 g), 5.02 g (-6.89 g, -3.14 g), 2.64 g (-4.65 g, -0.63 g) and 2.9 g (-4.8 g, 1 g) decreases, respectively, in birth weight. With each interquartile range increment in NO2 concentration was associated with an 8.05 g (6.24 g, 9.85 g) increase in birth weight. In the first trimester, only the PM2.5 exposure seemed to be associated with the greatest decline in birth weight. After adjustment for co-pollutant, both PM2.5 and SO2 were still associated with birth weight, except for CO for O3 adjustment, O3 for SO2 adjustment, and O3 for NO2 adjustment. Maternal exposure to air pollution may be associated with a decrease of birth weight, but the contribution of various pollutants is necessary to verify by future research.