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Objective To identify chromosomal regions harboring quantitative trait loci for waist circumference (WC) and body mass index (BMI). Design and Methods A genome-wide linkage scan and regional association study WC and BMI among 633 Chinese families was conducted. Results A significant linkage signal for WC was observed at 22q13.31-22q13.33 in the overall analysis (LOD = 3.13). Follow-up association study of 22q13.31-13.33 revealed an association between the TBC1D22A gene marker rs16996195 and WC (false discovery rate [FDR]-Q < 0.05). In gender-stratified analysis, suggestive linkage signals were attained for WC at 2p24.3-2q12.2 and 22q13.33 among females (LOD = 2.54 and 2.15, respectively). Among males, 6q12-6q13 was suggestively linked to BMI (LOD = 2.03). Single marker association analyses at these regions identified male-specific relationships of six single nucleotide polymorphisms (SNPs) at 2p24.3-2q12.2 (rs100955, rs13020676, rs13014034, rs12990515, rs17024325, and rs2192712) and five SNPs at 6q12-6q13 (rs7747318, rs7767301, rs12197115, rs12203049, and rs9454847) with the obesity-related phenotypes (all FDR-Q < 0.05). At chromosome 6q12-6q13, markers rs7755450 and rs11758293 predicted BMI in females (both FDR-Q < 0.05). Conclusions Genomic regions on chromosomes 2, 6, and 22 which may harbor important obesity-susceptibility loci were described. Follow-up study of these regions revealed several novel variants associated with obesity related traits. Future work to confirm these promising findings is warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP). METHODS After a 3-day baseline examination, during which time the usual diet was consumed, 1,906 Chinese participants received a 7-day low-sodium diet (51.3 mmol of sodium/day) followed by a 7-day high-sodium diet (307.8 mmol of sodium/day). BP measurements were obtained at baseline and at the end of each intervention using a random-zero sphygmomanometer. RESULTS The DDAH1 rs11161637 variant was associated with reduced BP salt sensitivity, conferring attenuated systolic BP (SBP) and mean arterial pressure (MAP) decreases from baseline to the low-sodium intervention (both P = 2×10−4). Examination of genotype–sex interactions revealed that this relation was driven by the strong associations observed in men (P for interactions = 1.10×10−4 and 0.008, respectively). When switching from the low- to high-sodium intervention, increases in diastolic BP (DBP) and MAP were attenuated by the COL18A1 rs2838944 minor A allele (P = 1.41×10−4 and 1.55×10−4, respectively). Conversely, the VWF rs2239153 C variant was associated with increased salt sensitivity, conferring larger DBP and MAP reductions during low-sodium intervention (P = 1.22×10−4 and 4.44×10−5, respectively). Ten variants from 3 independent SELE loci displayed significant genotype–sex interactions on DBP and MAP responses to low-sodium (P for interaction = 1.56×10−3 to 1.00×10−4). Among men, minor alleles of 4 correlated markers attenuated BP responses to low-sodium intake, whereas minor alleles of another 4 correlated markers increased BP responses. No associations were observed in women for these variants. Further, qualitative interactions were shown for 2 correlated SELE markers. CONCLUSIONS These data support a role for the endothelial system genes in salt sensitivity. [ABSTRACT FROM AUTHOR]

Small RNAs, including short interfering RNAs (siRNAs) and microRNAs (miRNAs), are ubiquitous, versatile repressors of gene expression in plants, animals, and many fungi. They can trigger destruction of homologous mRNA or inhibition of cognate mRNA translation and play an important role in maintaining the stable state of chromosome structure and regulating the expression of protein-coding genes. Furthermore, the recent research showed that there exists close relationship between small RNAs and human diseases. Several human diseases have surfaced in which miRNAs or their machinery might be implicated, such as some neurological diseases and cancers. The specificity and potency of small RNAs suggest that they might be promising as therapeutic agents. This article will review the role of small RNAs in some human diseases etiology and investigations of taking siRNAs as therapeutic tools for treating viral infection, cancer, and other diseases. We also discuss the potential of miRNAs in gene therapy. © 2004 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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Trials of retroviral vector-mediated human β-globin gene transfer were hampered by low titers, unstable vector transmission, and low-level expression of transferred gene. With the goal of optimizing the retrovirally encoded human β-globin gene expression cassette for gene therapy of β-thalassemia, we generated 3 series of vector constructs (a total of 12 constructs) and investigated the effects of the proximal promoter, 3′-enhancer, and derivatives from the β-locus control region or α-major regulatory element on virus titer, vector transmission stability, and gene expression. The virus titers for 9 of the 12 vector constructs ranged between 2.8×104 cfu/mL and 1.0×106 cfu/mL. We found that proviral DNA was intact in most G418-resistant murine erythroleukemia (MEL) cell clones for 5 vector constructs, while obvious genetic instability was observed for 4 other vector constructs. MEL cells harboring the intact provirus were induced to differentiate, and human β-globin gene expression was analyzed with RNase protection assay. The percentage of human β-globin transcript relative to endogenous murine α-globin transcript were 101.8±64.3% ( n=10), 40.1±28.7% ( n=4), 31.1±31.9% ( n=12), 52.4±11.2% ( n=12), and 53.6±8.6% ( n=12) for the 5 constructs, respectively, demonstrating the development of optimized retroviral vectors for β-globin gene therapy with murine erythroid cell lines as a model. Unexpectedly, we also documented that the point mutation 8700(C→T) in DNase I hypersensitive site 2 (HS2) core fragment might contribute to low-level expression of the human β-globin gene, based on a comparison of results from transfected and transduced MEL cells and sequence analysis of proviral DNA. [ABSTRACT FROM AUTHOR]

Special oligonucleotides for targeted gene correction have attracted increasing attention recently, one of which is the chimeric RNA·DNA oligonucleotide (RDO) system. RDOs for targeted gene correction were first designed in 1996, and are typically 68 nucleotides in length including continuous RNA and DNA sequences (RNA is 2′-O-methyl-modified). They have a 25 bp double stranded region homologous to the targeted gene, two hairpin ends of T loop and a 5 bp GC clamp, that give the molecule much greater stability [ Fig. 1]. One mismatch site in the middle of the double-stranded region is designed for targeted gene therapy. RDOs have been used recently for targeted gene correction of point mutations both in vitro and in vivo , but many problems must be solved before clinical application. One of the solutions is to optimize the delivery vectors for RDOs. To date, few RDO delivery systems have been used. Therefore, new vectors should be tried for RDO transfer, such as the use of nanoparticles. Additionally, different kinds of modifications should be applied to RDO carrier systems to increase the total correction efficiency in vivo . Only with the development of delivery systems can RDOs be used for gene therapy, and successfully applied to functional genomics. [ABSTRACT FROM AUTHOR]

Mutations in gene sequence can cause many genetic disorders, and researchers have attempted to develop treatments or cures at the DNA level for these diseases. Several strategies including triple-helix-forming oligonucleotides (TFOs), chimeric RNA/DNA oligonucleotide (RDO), and short single-stranded oligodeoxynucleotide (ODN) have been used to correct the dysfunctional genes in situ in the chromosome. Experimental data from cells and animal models suggest that all these strategies can repair the mutations in situ at DNA level. More effective structures of oligonucleotide, efficient delivery systems, and gene correction efficiency should be improved. Development of these strategies holds great potentials for treatments of genetic defects and other disorders. [ABSTRACT FROM AUTHOR]

The human β-globin locus is a classic model of the eukaryotic multigene family with tissue- and temporally specific expression. Over the past few years, great advances have been achieved in studies of β-globin locus regulation. The dominant role of the β-globin locus control region (LCR) in chromatin opening and developmental switching has been challenged, and elements beyond the LCR have been studied in depth. More recently, the fields of research have been expanded to intergenic transcription, nuclear localization and histone modification. Several models have been proposed to elucidate the regulation mechanism; among them, the looping and linking models are the most prevalent. Different models are the summarization of the observations made at different times and a persuasive model must be based on a systematic understanding of the numerous observations. The objective of this review is to provide an overview of progress in the area of β-globin regulation and then to discuss models for it. [ABSTRACT FROM AUTHOR]

Using ligation-mediated polymerase chain reaction and in vivo footprinting methods to study the status of DNA–protein interactions at hypersensitive site 3.5 (HS3.5) of the locus control region in K562 and HEL cells, we found that there was protein occupancy in vivo at HS3.5 in both cell lines and the status of DNA–protein interaction was different between K562 and HEL. These data provide direct evidence that specific nuclear factor – DNA complexes form in vivo at functionally important sequence motifs of the HS3.5 in erythroid cells. This indicates that HS3.5 may play an important role in the regulation of the β-globin gene cluster. K562 is a human erythroleukemia cell line in which the embryonic ℇ-globin gene is predominantly expressed, while the HEL cell line expresses predominantly the fetal β-globin genes. Thus, HS3.5 might also be involved in the regulation of developmental stage-specific expression of β-globin genes. Our results are also consistent with the model that each hypersensitive site acts as a functional unit and HS3.5 may facilitate the formation of the HS3 functional unit.Key words: β-globin gene, hypersensitive site, phylogenetic footprint, differential phylogenetic footprint, in vivo footprinting, developmental regulation.L'amplification en chaîne par polymérase et la méthode d'empreinte sur l'ADN in vivo ont été utilisées pour étudier les interactions entre des protéines et l'ADN au site hypersensible 3.5 (HS3.5) de la région de régulation du locus dans des cellules K562 et HEL. Les résultats montrent que des protéines sont liées au site HS3.5 in vivo dans les deux lignées cellulaires et que l'interaction des protéines avec l'ADN diffère entre les cellules K562 et HEL. Ces résultats sont une preuve directe que des complexes entre des facteurs nucléaires spécifiques et l'ADN se forment in vivo sur des motifs de la séquence du site HS3.5 ayant une importance fonctionnelle dans les cellules érythrocytaires. Cela indique que le site HS3.5 jouerait un rôle important dans la régulation du groupe de gènes de la globine β. La lignée K562 de cellules érythroleucémiques humaines exprime principalement le gène de la globine ℇ embryonnaire, tandis que la lignée de cellules HEL exprime surtout les gènes de la globine γ foetale. Le site HS3.5 pourrait également intervenir dans la régulation de l'expression des gènes de la globine β au cours d'étapes spécifiques du développement. Nos résultats sont également en accord avec le modèle selon lequel chaque site hypersensible est une unité fonctionnelle et que le site HS3.5 faciliterait la formation de l'unité fonctionnelle HS3.Mots clés : gène, globine β, site hypersensible, empreinte phylogénétique, empreinte phylogénétique différentielle, empreinte sur l'ADN in vivo, régulation du développement.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]

Adeno-associated virus (AAV) is a promising viral vector in treating many kinds of hereditary diseases. The broad host range, low level of immune response, and longevity of gene expression observed with this vector have enabled the initiation of a number of clinical trials using this gene delivery system. Another potential benefit of AAV vectors is their ability to integrate site-specifically in the presence of Rep proteins. However, this virus is not well characterized. To obtain high level, persistent expression of the foreign gene, some problems should be solved. In this article, we will describe the advances in some fields of recombinant AAV technology that overcome certain limitations of the vector as a gene delivery system, such as the transduction efficiency, the production, the package capacity, and elimination of immune responses, as well as the applications involving these recombinant vectors for the treatment of some diseases. [ABSTRACT FROM AUTHOR]

The human globin gene cluster, which represents a prototypical eukaryotic multigene locus, has been investigated for more than two decades and is classic model for coordinate control of tissue-specific gene expression. It is well known that globin gene expression is restricted to specific tissues and that globin genes are sequentially switched on during development. What intricate regulatory mechanisms account for tissue-specific transcriptional control of globin gene expression? Previous studies have focused on the interactions of trans-acting factors and cis-acting elements including the locus control region (LCR), which is considered a potent enhancer in globin gene switching. More recent studies have not only focused on the local DNA regulatory elements but also on remodelling of chromatin and transcription at the globin gene cluster within the native genomic context. Moreover, several studies have presented extensive data that address whether the LCR is required to open the chromatin. Although there is increased insight into the regulation of the β-globin gene switching, many aspects relating to the developmental activation of distinct globin genes remain elusive. [ABSTRACT FROM AUTHOR]

Tc1/mariner transposons are widespread in the eukaryotes. In vitro transposition test indicated that the transposase is the only protein that is needed in transpositions. It was shown later that the reconstructed Tc1-like transposon, “sleeping beauty” in fish, and the Tc1 transposon in C. elegans jumps in human cells. This discovery indicates that the Tc1/mariner transposon may be engineered as a somatic gene therapy vector if coupled with an efficient gene delivery system. We introduced the Tc1 transposon from C. elegans into different mammalian cell lines and detected the transposition events, indicating that Tc1 transposon functions in different mammalian cells. Interestingly, a high inversion frequency of the transposon was also detected, suggesting that this type of transposon may add variations to host genome when it is horizontally transferred into a new species. [ABSTRACT FROM AUTHOR]

As a new developmental vector system, the bacterial artificial chromosome (BAC) has been used widely in constructing genomic libraries and in generating transgenic animals. Isolation of the BAC insert end is useful to analyze the BAC clone. Here, we describe a fast and efficient method to obtain the BAC end by ligating the BAC fragments digested with Not I and another selected restriction enzyme into universal cloning vector, followed by determining the correct clones with HindIII digestion. Further DNA sequencing analysis verified the results mentioned above. [ABSTRACT FROM AUTHOR]

The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE2 and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4. The use of nonsteroidal anti-inflammatory drugs inhibiting COX-1/2 is associated with an increased risk of heart failure. Here the authors show that mPGES-1, a therapeutic target downstream of COX enzymes, protects from cardiac ischemia/reperfusion injury, limiting leukocyte-endothelial interactions and preserving microvascular perfusion partly via the endothelial EP4 receptor. [ABSTRACT FROM AUTHOR]

Background: Mouse somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors known to regulate pluripotency, including Oct4, Sox2, Klf4, and c-Myc. It has been reported that Sirtuin 6 (Sirt6), a member of the sirtuin family of NAD+-dependent protein deacetylases, is involved in embryonic stem cell differentiation. However, whether and how Sirt6 influences epigenetic reprogramming remains unknown. Methods: Mouse embryonic fibroblasts isolated from transgenic Oct4-GFP reporter mice with or without Sirt6 were used for reprogramming by Yamanaka factors. Alkaline phosphatase-positive and OCT4-GFP-positive colony were counted to calculate reprogramming efficiency. OP9 feeder cell co-culture system was used to measure the hematopoietic differentiation from mouse ES and iPS cells. RNA sequencing was measured to identify the differential expressed genes due to loss of Sirt6 in somatic and pluripotent cells. Results: In this study, we provide evidence that Sirt6 is involved in mouse somatic reprogramming. We found that loss of function of Sirt6 could significantly decrease reprogramming efficiency. Furthermore, we showed that Sirt6-null iPS-like cell line has intrinsically a differentiation defect even though the establishment of normal self-renewal. Particularly, by performing transcriptome analysis, we observed that several pluripotent transcriptional factors increase in knockout cell line, which explains the underlying loss of pluripotency in Sirt6-null iPS-like cell line. Conclusions: Taken together, we have identified a new regulatory role of Sirt6 in reprogramming and maintenance of pluripotency. [ABSTRACT FROM AUTHOR]

Accumulating data from genome-wide association studies (GWAS) have provided a collection of novel candidate genes associated with complex diseases, such as atherosclerosis. We identified an atherosclerosis-associated single-nucleotide polymorphism (SNP) located in the intron of the long noncoding RNA (lncRNA) LINC00305 by searching the GWAS database. Although the function of LINC00305 is unknown, we found that LINC00305 expression is enriched in atherosclerotic plaques and monocytes. Overexpression of LINC00305 promoted the expression of inflammation-associated genes in THP-1 cells and reduced the expression of contractile markers in co-cultured human aortic smooth muscle cells (HASMCs). We showed that overexpression of LINC00305 activated nuclear factor-kappa beta (NF-κB) and that inhibition of NF-κB abolished LINC00305-mediated activation of cytokine expression. Mechanistically, LINC00305 interacted with lipocalin-1 interacting membrane receptor (LIMR), enhanced the interaction of LIMR and aryl-hydrocarbon receptor repressor (AHRR), and promoted protein expression as well as nuclear localization of AHRR. Moreover, LINC00305 activated NF-κB exclusively in the presence of LIMR and AHRR. In light of these findings, we propose that LINC00305 promotes monocyte inflammation by facilitating LIMR and AHRR cooperation and the AHRR activation, which eventually activates NF-κB, thereby inducing HASMC phenotype switching. [ABSTRACT FROM AUTHOR]

The homeodomain transcription factor Nkx2.5/Csx is critically essential for heart specification, morphogenesis, and homeostasis. Acetylation/deacetylation is important for the localization, stability and activation of transcription factors. It remains unknown how Nkx2.5 is deacetylated and how Nkx2.5 acetylation determines its activity. In this study, we provide evidence that the NAD+-dependent class III protein deacetylase SIRT1 deacetylates Nkx2.5 in cardiomyocytes and represses the transcriptional activity of Nkx2.5. We show that SIRT1 interacts with the C-terminus of Nkx2.5 and deacetylates Nkx2.5 at lysine 182 in the homeodomain. The mutation of Nkx2.5 at lysine 182 reduces its transcriptional activity. Furthermore, SIRT1 inhibits the transcriptional activity of Nkx2.5 and represses the expression of its target genes partly by reducing Nkx2.5 binding to its co-factors, including SRF and TBX5. Taken together, these findings demonstrate that SIRT1 deacetylates Nkx2.5 and inhibits the transcriptional activity of Nkx2.5. [ABSTRACT FROM AUTHOR]

Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age‐dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N‐acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo‐insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies. [ABSTRACT FROM AUTHOR]

The current study comprehensively examined the association between common genetic variants of the kallikrein-kinin system (KKS) and blood pressure salt sensitivity. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1,906 Han Chinese participants recruited from 2003 to 2005. Blood pressure was measured by using a random-zero sphygmomanometer through the study. A total of 205 single nucleotide polymorphisms (SNPs) covering 11 genes of the KKS were selected for the analyses. Genetic variants of the bradykinin receptor B2 gene (BDKRB2) and the endothelin converting enzyme 1 gene (ECE1) showed significant associations with the salt-sensitivity phenotypes even after adjustment for multiple testing. Compared with the major G allele, the BDKRB2 rs11847625 minor C allele was significantly associated with increased systolic blood pressure responses to low-sodium intervention (P = 0.0001). Furthermore, a haplotype containing allele C was associated with an increased systolic blood pressure response to high-sodium intervention (P = 0.0009). Seven highly correlated ECE1 SNPs were shown to increase the diastolic blood pressure response to low-sodium intervention (P values ranged from 0.0003 to 0.002), with 2 haplotypes containing these 7 SNPs also associated with this same phenotype (P values ranged from 0.0004 to 0.002). In summary, genetic variants of the genes involved in the regulation of KKS may contribute to the salt sensitivity of blood pressure. [ABSTRACT FROM PUBLISHER]

The authors conducted a genome-wide linkage scan and positional association analysis to identify the genetic determinants of salt sensitivity of blood pressure (BP) in a large family-based, dietary-feeding study. The dietary intervention was conducted among 1,906 participants in rural China (2003–2005). A 7-day low-sodium intervention was followed by a 7-day high-sodium intervention. Salt sensitivity was defined as BP responses to low- and high-sodium interventions. Signals of the logarithm of the odds to the base 10 (LOD ≥ 3) were detected at 33–42 centimorgans of chromosome 2 (2p24.3-2p24.1), with a maximum LOD score of 3.33 for diastolic blood pressure responses to high-sodium intervention. LOD scores were 2.35–2.91 for mean arterial pressure (MAP) and 0.80–1.49 for systolic blood pressure responses in this region, respectively. Correcting for multiple tests, single nucleotide polymorphism (SNP) rs11674786 (2.7 kilobases upstream of the family with sequence similarity 84, member A, gene (FAM84A)) in the linkage region was significantly associated with diastolic blood pressure (P = 0.0007) and MAP responses (P = 0.0007), and SNP rs16983422 (2.8 kilobases upstream of the visinin-like 1 gene (VSNL1)) was marginally associated with diastolic blood pressure (P = 0.005) and MAP responses (P = 0.005). An additive interaction between SNPs rs11674786 and rs16983422 was observed, with P = 7.00 × 10−5 and P = 7.23 × 10−5 for diastolic blood pressure and MAP responses, respectively. The authors concluded that genetic region 2p24.3-2p24.1 might harbor functional variants for the salt sensitivity of BP. [ABSTRACT FROM PUBLISHER]

Cellular senescence (CS), a state of permanent growth arrest, is intertwined with tumorigenesis. Due to the absence of specific markers, characterizing senescence levels and senescence-related phenotypes across cancer types remain unexplored. Here, we defined computational metrics of senescence levels as CS scores to delineate CS landscape across 33 cancer types and 29 normal tissues and explored CS-associated phenotypes by integrating multiplatform data from ~20 000 patients and ~212 000 single-cell profiles. CS scores showed cancer type-specific associations with genomic and immune characteristics and significantly predicted immunotherapy responses and patient prognosis in multiple cancers. Single-cell CS quantification revealed intra-tumor heterogeneity and activated immune microenvironment in senescent prostate cancer. Using machine learning algorithms, we identified three CS genes as potential prognostic predictors in prostate cancer and verified them by immunohistochemical assays in 72 patients. Our study provides a comprehensive framework for evaluating senescence levels and clinical relevance, gaining insights into CS roles in cancer- and senescence-related biomarker discovery. [ABSTRACT FROM AUTHOR]

Abstract: ATP-sensitive potassium channel (KATP) is one kind of inwardly rectifying channel composed of two kinds of subunits: the pore forming subunits and the regulatory subunits. KATP channels exist in the sarcolemmal, mitochondrial and nuclear membranes of various tissues. Cell metabolism regulates KATP gene expression and metabolism products regulate the channel by direct interactions, while KATP controls membrane potentials and regulate cell activities including energy metabolism, apoptosis and gene expression. KATP channels from different cell organelles are linked by some signal molecules and they can respond to common stimulation in a coordinate way. In the cardiovascular system KATP has important functions. The most prominent is that opening of this channel can protect cardiac myocytes against ischemic injuries. The sarcolemmal KATP may provide a basic protection against ischemia by energy sparing, while both the sarcolemmal KATP and mitochondrial KATP channels are necessary for the ischemia preconditioning. KATP channels also have important functions including homeostasis maintenance and vascular tone regulation under physiological conditions. Further elucidation of the role of KATP in the cardiovascular system will help us to regulate cell metabolism or prevent damage caused by abnormal channel functions. [Copyright &y& Elsevier]

Cardiovascular diseases are a serious threat to human health, especially in the elderly. Vascular aging makes people more susceptible to cardiovascular diseases due to significant dysfunction or senescence of vascular cells and maladaptation of vascular structure and function; moreover, vascular aging is currently viewed as a modifiable cardiovascular risk factor. To emphasize the relationship between senescent cells and vascular aging, we first summarize the roles of senescent vascular cells (endothelial cells, smooth muscle cells and immune cells) in the vascular aging process and inducers that contribute to cellular senescence. Then, we present potential strategies for directly targeting senescent cells (senotherapy) or preventively targeting senescence inducers (senoprevention) to delay vascular aging and the development of age-related vascular diseases. Finally, based on recent research, we note some important questions that still need to be addressed in the future. The relationships among cellular senescence inducers, senescent cells and vascular aging. Telomere-dependent replicative senescence and stress-induced premature senescence have different senescence inducers. These inducers comprise a complicated network and promote cell senescence in aortas. Senescent vascular cells lead to typical pathological changes of vascular aging by abnormal function and molecular expression, which further contribute to related vascular diseases. Cell senescence and other pathological changes induced the abnormalities in vascular structure and function, which are direct manifestations of vascular aging and related diseases. More details are provided in the main text. Abbreviation: ECs: Endothelium cells; ECM: Extracellular matrix; IIS: Impaired immunosurveillance; RAAS: Renin-angiotensin-aldosterone system; SASP: Senescence associated secretory phenotype; VSMCs: Vascular smooth muscle cells. [Display omitted] • Vascular aging is currently viewed as a modifiable cardiovascular risk factor. • Vascular cells senescence contributes to the progression of vascular aging along with age-related disorders. • The clearance of senescent cells by senotherapy or senoprevention is a candidate intervention to decelerate vascular aging. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs) are a newly identified and surprisingly large class of endogenous tiny regulatory RNAs. They exhibit various expressional patterns and are highly conserved across species. Recently, several regulatory targets of miRNAs have been predicted. Functional analysis of the potential targets indicated that miRNAs may be involved in a wide range of pivotally biological events. The nature of miRNAs and their intersection with small interfering RNAs endow them with many regulatory advantages over proteins and make them a potent and novel means to regulate gene expression at almost all levels. Here we argue that miRNAs are key participants in gene regulatory network. [Copyright &y& Elsevier]

Due to the increased safety and efficiency of virus vectors, virus vector-mediated gene therapy is now widely used for various diseases, including monogenic diseases, complex disorders, and infectious diseases. Recent gene therapy trials have shown significant therapeutic benefits, and Chinese researchers have contributed significantly to this progress. This review highlights disease applications and strategies for virus vector-mediated gene therapy in preclinical studies and clinical trials in China. [ABSTRACT FROM AUTHOR]

Cell senescence, which is an irreversible state of cell proliferative arrest, has emerged as a potentially important contributor to tissue dysfunction and organismal ageing. Cell senescence is triggered by a variety of senescence stressors, which affect gene expression and multiple signalling pathways that give rise to various senescence phenotypes. Epigenetic mechanisms, as critical regulators of chromosomal architecture and gene expression, have added an extra dimension to the molecular mechanisms of cell senescence. Cell senescence is accompanied by changes in DNA methylation, histone-associated epigenetic processes, chromatin remodelling and ncRNA expression. Those senescence-associated epigenetic alterations interact with the senescence regulatory programme networks and lead to various cell senescence phenotypes. This review provides a comprehensive overview of epigenetic changes and their effects on cell senescence. The differences in epigenetic alterations among different types of senescence are also discussed. Furthermore, we summarise the interactions among different epigenetic mechanisms during cell senescence and analyse the possibility of using epigenetic signatures as biomarkers and therapeutic targets for the treatment of senescence-associated diseases. [ABSTRACT FROM AUTHOR]

The inactivation of plasminogen activator inhibitor-1 ( PAI-1) has been shown to exert beneficial effects in age-related vascular diseases. Limited information is available on the molecular mechanisms regarding the negatively regulated expression of PAI-1 in the vascular system. In this study, we observed an inverse correlation between SIRT1, a class III histone deacetylase, and PAI-1 expression in human atherosclerotic plaques and the aortas of old mice, suggesting that internal negative regulation exists between SIRT1 and PAI-1. SIRT1 overexpression reversed the increased PAI-1 expression in senescent human umbilical vein endothelial cells ( HUVECs) and aortas of old mice, accompanied by decreased SA-β-gal activity in vitro and improved endothelial function and reduced arterial stiffness in vivo. Moreover, the SIRT1-mediated inhibition of PAI-1 expression exerted an antisenescence effect in HUVECs. Furthermore, we demonstrated that SIRT1 is able to bind to the PAI-1 promoter, resulting in a decrease in the acetylation of histone H4 lysine 16 (H4K16) on the PAI-1 promoter region. Thus, our findings suggest that the SIRT1-mediated epigenetic inhibition of PAI-1 expression exerts a protective effect in vascular endothelial senescence. [ABSTRACT FROM AUTHOR]

Angiotensin II (AngII) induces the development of vascular hypertrophy and hypertension. We have shown previously that overexpression of class III deacetylase SIRT1 inhibits AngII-induced hypertrophy in vascular smooth muscle cells (VSMCs). However, the direct role of SIRT1 in VSMCs in response to AngII infusion in vivo remains unclear. Here, we found that the expression and activity of SIRT1 in mouse aortas was decreased significantly by AngII infusion. VSMC-specific SIRT1 transgene (SV-Tg) prevented the increase in systolic blood pressure (SBP) caused by AngII infusion without affecting heart function in mice. SIRT1 overexpression alleviated vascular remodeling in mouse thoracic and renal aortas induced by AngII infusion, and significantly inhibited reactive oxygen species (ROS) generation, vascular inflammation, and collagen synthesis in arterial walls. Reduced expression of transforming growth factor-β 1 (TGF-β1) was also observed in the aortas of AngII-infused SV-Tg mice. Moreover, SIRT1 overexpression decreased AngII-increased binding of nuclear factor-κB on its specific binding sites on TGF-β1 promoter. Taken together, these data demonstrate that SIRT1 overexpression in VSMCs reduces SBP and inhibits AngII-induced vascular remodeling in mice. The inhibition of vascular remodeling contributes, at least in part, to the antihypertensive effect of SIRT1. Key message: [ABSTRACT FROM AUTHOR]

Nkx2.5 plays protective roles in cardiac homeostasis and survival in the postnatal hearts. However, the underlying molecular mechanisms that mediate the protective functions of Nkx2.5 remain unknown. Here, we showed that Nkx2.5 was downregulated in response to various stresses and was required for protection against the stress-induced apoptosis of cardiomyocytes. SIRT1, a member of the sirtuin family of proteins, was found to be a direct transcriptional target of Nkx2.5 and was required for the Nkx2.5-mediated protection of cardiomyocytes from doxorubicin (DOX)-induced apoptosis. Moreover, using chromatin immunoprecipitation assays, we found that Nkx2.5 was able to bind to the SIRT1 promoter and that this binding was significantly decreased in DOX-treated mouse hearts. Furthermore, the cardiac-specific overexpression of SIRT1 decreased the DOX-induced apoptosis of cardiomyocytes in SIRT1 transgenic mouse hearts compared with the hearts of their wild-type littermates. These findings demonstrate that SIRT1 acts as a direct transcriptional target of Nkx2.5 that maintains cardiomyocyte homeostasis and survival. [ABSTRACT FROM AUTHOR]