Mitochondria are perhaps the most sophisticated and dynamic responsive sensing systems in eukaryotic cells. The role of mitochondria goes beyond their capacity to create molecular fuel and includes the generation of reactive oxygen species, the regulation of calcium, and the activation of cell death. In endothelial cells, mitochondria have a profound impact on cellular function under both healthy and diseased conditions. In this review, we summarize the basic functions of mitochondria in endothelial cells and discuss the roles of mitochondria in endothelial dysfunction and vascular diseases, including atherosclerosis, diabetic vascular dysfunction, pulmonary artery hypertension, and hypertension. Finally, the potential therapeutic strategies to improve mitochondrial function in endothelial cells and vascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants and calorie restriction.

Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

Abstract-Pathological cardiac hypertrophy is a major risk factor for heart failure. In this study, we identified interferon regulatory factor 9 (IRF9), a member of the IRF family, as a previously unidentified negative regulator of cardiac hypertrophy. The level of IRF9 expression was remarkably elevated in the hearts from animals with aortic bandinginduced cardiac hypertrophy. IRF9-deficient mice exhibited pronounced cardiac hypertrophy after pressure overload, as demonstrated by increased cardiomyocyte size, extensive fibrosis, reduced cardiac function, and enhanced expression of hypertrophy markers, whereas transgenic mice with cardiac-specific overexpression of murine IRF9 exhibited a significant reduction in the hypertrophic response. Mechanistically, IRF9 competes with p300 for binding to the transcription activation domain of myocardin, a coactivator of serum response factor (SRF). This interaction markedly suppresses the transcriptional activity of myocardin because IRF9 overexpression strongly inhibits the ability of myocardin to activate CArG box-dependent reporters. These results provide compelling evidence that IRF9 inhibits the development of cardiac hypertrophy by suppressing the transcriptional activity of myocardin in the heart. (Hypertension. 2014;63:119-127.) • Online Data Supplement

Precise regulation of mtDNA transcription and oxidative phosphorylation (OXPHOS) is crucial for human health. As a component of mitochondrial contact site and cristae organizing system (MICOS), Mic60 plays a central role in mitochondrial morphology. However, it remains unclear whether Mic60 affects mitochondrial transcription. Here, we report that Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Furthermore, we found that Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities. Importantly, Mic60 deficiency decreased TFAM binding and mitochondrial RNA polymerase (POLRMT) recruitment to the mtDNA promoters. In addition, through mtDNA immunoprecipitation (mIP)-chromatin conformation capture (3C) assays, we found that Mic60 interacted with mtDNA and was involved in the architecture of mtDNA D-loop region. Taken together, our findings reveal a previously unrecognized important role of Mic60 in mtDNA transcription.

356D espite recent treatment advances, chronic heart failure still carries a poor prognosis and continues to be a major health challenge in worldwide.1,2 Cardiac hypertrophy, occurring in response to pathological stimuli, such as hypertension or ischemia, is a major risk factor for the development of heart failure.3 Numerous intracellular signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade and the mitogen-activated protein kinase (MAPK) pathway initiate and propagate hypertrophic myocardial growth. 4,5 After PI3K activation by cardiac hypertrophic stress, phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and thereby activates AKT, which subsequently induces hypertrophy via regulating downstream molecules, including inactivation of glycogen synthase kinase-3β (GSK3β) and activation of mammalian target of rapamycin (mTOR) and p70S6 kinase. [5][6][7] However, the underlying mechanisms of cardiac hypertrophy and the resultant heart failure remain unclear.Tumor necrosis factor receptor-associated factors (TRAFs) are a family of cytoplasmic adaptor proteins with critical functions in the signaling pathways initiated by tumor necrosis factor receptors, toll-like receptors, and interleukin-1 receptors.8 Consistent with the functions of other TRAF family members, TRAF3 regulates the activities of several signaling pathways. However, TRAF3 has a unique manner of coordinating signaling events. Previous studies have demonstrated that TRAF3 degradation after CD40 engagement in B cells leads to the release of MAPK kinase kinase 1, transforming growth factor β-activated kinase 1, and nuclear factor-κB (NF-κB)-inducing kinase into the cytoplasm, ultimately leading to MAPK and IκB kinase-α (IKK-α) activation. 9,10 Other studies have reported that TRAF3 binds to PI3K 11,12 ; this binding is correlated with the level of TRAF3 ubiquitination, which is crucial for the effect of TRAF3 on CD40-associated AKT activation.11 Although the MAPK, NF-κB, and AKT signaling pathways all contribute to the development of cardiac Abstract-Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways.Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II-or phenylephrineinduced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli...

Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent stem cells (PSCs) is a central aim in T cell regenerative medicine. To date, preferentially reconstituting T lymphopoiesis in vivo from PSCs remains a practical challenge. Here we documented that synergistic and transient expression of Runx1 and Hoxa9 restricted in the time window of endothelial-tohematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iR9-PSC) in vitro induced preferential generation of engraftable hematopoietic progenitors capable of homing to thymus and developing into mature T cells in primary and secondary immunodeficient recipients. Single-cell transcriptome and functional analyses illustrated the cellular trajectory of T lineage induction from PSCs, unveiling the T-lineage specification determined at as early as hemogenic endothelial cell stage and identifying the bona fide pre-thymic progenitors. The induced T cells distributed normally in central and peripheral lymphoid organs and exhibited abundant TCRαβ repertoire. The regenerative T lymphopoiesis restored immune surveillance in immunodeficient mice. Furthermore, gene-edited iR9-PSCs produced tumor-specific T cells in vivo that effectively eradicated tumor cells. This study provides insight into universal generation of functional and therapeutic T cells from the unlimited and editable PSC source.

PurposeTo estimate the diagnostic accuracy of Xpert MTB/RIF, a systematic review and meta-analysis were carried out.MethodsUp to June 20, 2015, multiple databases were screened for relevant studies.ResultsAccordingly, 106 studies included 52,410 samples were selected. Diagnostic accuracy of Xpert MTB/RIF for TB detection was validated against either culture or a composite reference standard (CRS). Additionally, selected studies were further subgrouped in four groups based on sample’s type, subject’s age, status of HIV co-infection and smear-positivity. The overall pooled sensitivity and specificity of Xpert MTB/RIF was 0.85 (95% confidence interval [CI] 0.82–0.88) and 0.98 (95% CI 0.96–0.98), respectively, compared to culture; while it was 0.59 (95% CI 0.44–0.72) and 0.99 (95% CI 0.97–1.00) compared to CRS. The overall sensitivity was lower in countries with high TB prevalence than countries with middle/low prevalence (0.84, 95% CI: 0.80–0.88 versus 0.89, 95% CI: 0.84–0.93). Furthermore, Xpert MTB/RIF has higher sensitivity in patients with positive smears (0.99, 95% CI 0.97–0.99), in patients with pulmonary TB samples (0.87, 95% CI 0.83–0.90), in adults (0.82, 95% CI 0.76–0.86) and in HIV-positive patients (0.81, 95% CI 0.73–0.87).ConclusionsTaken together, Xpert MTB/RIF is a quick and accurate diagnostic assay for TB which will significantly help the physicians to make their clinical decisions.

Gene therapy is one of the frontiers of modern medicine. Adeno-associated virus (AAV)-mediated gene therapy is becoming a promising approach to treat a variety of diseases and cancers. AAV-mediated cancer gene therapies have rapidly advanced due to their superiority to other gene-carrying vectors, such as the lack of pathogenicity, the ability to transfect both dividing and non-dividing cells, low host immune response, and long-term expression. This article reviews and provides up to date knowledge on AAV-mediated cancer gene therapy.