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1.
Eur Heart J ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34534287

RESUMO

AIMS: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. METHODS AND RESULTS: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. CONCLUSION: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.

2.
J Mol Cell Cardiol ; 162: 10-19, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474073

RESUMO

Our previous study has revealed that exosomes from adipose-derived stem cells (ASCs) promote angiogenesis in subcutaneously transplanted gels by delivery of microRNA-31 (miR-31) which targets factor inhibiting hypoxia-inducible factor-1 (FIH1) in recipient cells. Here we hypothesized that ASC exosomes alleviate ischemic diseases through miR-31/FIH1/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. Exosomes from ASCs were characterized with nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting analysis for exosomal markers. Results from immunoblotting and laser imaging of ischemic mouse hindlimb revealed that miR-31 enriched ASC exosomes inhibited FIH1 expression and enhanced the blood perfusion, respectively. These effects were impaired when using miR-31-depleted exosomes. Immunohistochemistry analysis showed that administration of exosomes resulted in a higher arteriole density and larger CD31+ area in ischemic hindlimb than miR-31-delpleted exosomes. Similarly, knockdown of miR-31 in exosomes reduced the effects of the exosomes on increasing ventricular fraction shortening and CD31+ area, and on decreasing infarct size. Exosomes promoted endothelial cell migration and tube formation. These changes were attenuated when miR-31 was depleted in the exosomes or when FIH1 was overexpressed in the endothelial cells. Furthermore, the results from immunocytochemistry, co-immunoprecipitation, and luciferase reporter assay demonstrated that the effects of exosomes on nuclear translocation, binding with co-activator p300, and activation of HIF-1α were decreased when miR-31 was depleted in the exosomes or FIH1 was overexpressed. Our findings provide evidence that exosomes from ASCs promote angiogenesis in both mouse ischemic hindlimb and heart through transport of miR-31 which targets FIH1 and therefore triggers HIF-1α transcriptional activation.

3.
Hypertension ; : HYPERTENSIONAHA12117597, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34488438

RESUMO

While exogenous administration of recombinant erythropoietin has been associated with increased risk of hypertension, coronary artery disease, and mortality, it is not known if endogenous circulating erythropoietin level is associated with coronary artery disease and its risk factors. We measured and analyzed epidemiological and genetic associations of circulating plasma erythropoietin levels in 2 population cohorts, from China (N=4329) and the United States (N=3671). In vitro smooth muscle cell responses and in vivo murine studies of erythropoietin exposure were performed. Erythropoietin levels were positively and linearly associated with blood pressure traits and inversely associated with cholesterol levels and red cell indices. Higher erythropoietin level was associated with higher prevalence of hypertension (odds ratio, 1.20 [95% CI, 1.12-1.29], P=4.41×10-7) and coronary artery disease (odds ratio, 1.16 [95% CI, 1.00-1.34], P=0.046). In a discovery stage genetic association study of erythropoietin level, we identified a previously reported locus on chromosome 6 (rs7776054 near HBS1L-MYB, P=4.86×10-25) and a new locus on chromosome 4 (rs172629 near PDGFRA-KIT, P=2.1×10-8), which was independently replicated. Meta-analysis of discovery and replication genetic association results identified a locus on chromosome 22 (rs855791 near TMPRSS6, P=3.60×10-9). Erythropoietin administration, within a physiological range of hematocrit achieved, induced hypertension in vivo and increased contraction of vascular smooth muscle cells in vitro. In conclusion, endogenous circulating erythropoietin level is influenced by common genetic variation and is associated with blood pressure traits, hypertension, and coronary artery disease. Vascular effects of erythropoietin demonstrated in vitro and in vivo support a newly discovered mechanism of hypertension and cardiovascular risk with potential implications for erythropoietic support in the clinic.

4.
Circulation ; 144(14): 1145-1159, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34346740

RESUMO

BACKGROUND: Loeys-Dietz syndrome (LDS) is an inherited disorder predisposing individuals to thoracic aortic aneurysm and dissection. Currently, there are no medical treatments except surgical resection. Although the genetic basis of LDS is well-understood, molecular mechanisms underlying the disease remain elusive, impeding the development of a therapeutic strategy. In addition, aortic smooth muscle cells (SMCs) have heterogenous embryonic origins, depending on their spatial location, and lineage-specific effects of pathogenic variants on SMC function, likely causing regionally constrained LDS manifestations, have been unexplored. METHODS: We identified an LDS family with a dominant pathogenic variant in the TGFBR1 gene (TGFBR1A230T) causing aortic root aneurysm and dissection. To accurately model the molecular defects caused by this mutation, we used human induced pluripotent stem cells from a subject with normal aorta to generate human induced pluripotent stem cells carrying TGFBR1A230T, and corrected the mutation in patient-derived human induced pluripotent stem cells using CRISPR-Cas9 gene editing. After their lineage-specific SMC differentiation through cardiovascular progenitor cell (CPC) and neural crest stem cell lineages, we used conventional molecular techniques and single-cell RNA sequencing to characterize the molecular defects. The resulting data led to subsequent molecular and functional rescue experiments using activin A and rapamycin. RESULTS: Our results indicate the TGFBR1A230T mutation impairs contractile transcript and protein levels, and function in CPC-SMC, but not in neural crest stem cell-SMC. Single-cell RNA sequencing results implicate defective differentiation even in TGFBR1A230T/+ CPC-SMC including disruption of SMC contraction and extracellular matrix formation. Comparison of patient-derived and mutation-corrected cells supported the contractile phenotype observed in the mutant CPC-SMC. TGFBR1A230T selectively disrupted SMAD3 (SMAD family member 3) and AKT (AKT serine/threonine kinase) activation in CPC-SMC, and led to increased cell proliferation. Consistently, single-cell RNA sequencing revealed molecular similarities between a loss-of-function SMAD3 mutation (SMAD3c.652delA/+) and TGFBR1A230T/+. Last, combination treatment with activin A and rapamycin during or after SMC differentiation significantly improved the mutant CPC-SMC contractile gene expression and function, and rescued the mechanical properties of mutant CPC-SMC tissue constructs. CONCLUSIONS: This study reveals that a pathogenic TGFBR1 variant causes lineage-specific SMC defects informing the etiology of LDS-associated aortic root aneurysm. As a potential pharmacological strategy, our results highlight a combination treatment with activin A and rapamycin that can rescue the SMC defects caused by the variant.

5.
Thromb Haemost ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34428834

RESUMO

Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored. Utilizing stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs), we identified an increase of KLF11 expression under prothrombotic conditions both in vivo and in vitro. The expression change of thrombosis-related genes was determined by utilizing gain- and loss-of-function approaches to alter KLF11 expression in ECs. Among these genes, KLF11 significantly downregulated tumor necrosis factor-α (TNF-α)-induced tissue factor (TF) gene transcription. Using reporter gene assay, chromatin immunoprecipitation assay, and co-immunoprecipitation, we revealed that KLF11 could reduce TNF-α-induced binding of early growth response 1 (EGR1) to TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 knockout mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF gene transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against venous thrombosis, constituting a potential molecular target for treating thrombosis.

6.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34265237

RESUMO

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.


Assuntos
Aneurisma da Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Locos de Características Quantitativas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Estudos de Casos e Controles , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Cell Rep ; 36(4): 109420, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34320345

RESUMO

Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT. Agxt deletion in apolipoprotein E-deficient (Apoe-/-) mice decreases the glycine/oxalate ratio and increases atherosclerosis with induction of hepatic pro-atherogenic pathways, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, circulating and aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages are increased. Similar findings are observed following dietary oxalate overload in Apoe-/- mice. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, leading to increased CCL5. Conversely, AGXT overexpression in Apoe-/- mice increases the glycine/oxalate ratio and decreases aortic superoxide, CCL5, and atherosclerosis. Our findings uncover dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.

8.
JCI Insight ; 6(14)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34138755

RESUMO

Cancer cells reprogram cellular metabolism to maintain adequate nutrient pools to sustain proliferation. Moreover, autophagy is a regulated mechanism to break down dysfunctional cellular components and recycle cellular nutrients. However, the requirement for autophagy and the integration in cancer cell metabolism is not clear in colon cancer. Here, we show a cell-autonomous dependency of autophagy for cell growth in colorectal cancer. Loss of epithelial autophagy inhibits tumor growth in both sporadic and colitis-associated cancer models. Genetic and pharmacological inhibition of autophagy inhibits cell growth in colon cancer-derived cell lines and patient-derived enteroid models. Importantly, normal colon epithelium and patient-derived normal enteroid growth were not decreased following autophagy inhibition. To couple the role of autophagy to cellular metabolism, a cell culture screen in conjunction with metabolomic analysis was performed. We identified a critical role of autophagy to maintain mitochondrial metabolites for growth. Loss of mitochondrial recycling through inhibition of mitophagy hinders colon cancer cell growth. These findings have revealed a cell-autonomous role of autophagy that plays a critical role in regulating nutrient pools in vivo and in cell models, and it provides therapeutic targets for colon cancer.

9.
Biomaterials ; 274: 120874, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34051629

RESUMO

To address the clinical need for readily available small diameter vascular grafts, biomimetic tubular scaffolds were developed for rapid in situ blood vessel regeneration. The tubular scaffolds were designed to have an inner layer that is porous, interconnected, and with a nanofibrous architecture, which provided an excellent microenvironment for host cell invasion and proliferation. Through the synthesis of poly(spirolactic-co-lactic acid) (PSLA), a highly functional polymer with a norbornene substituting a methyl group in poly(l-lactic acid) (PLLA), we were able to covalently attach biomolecules onto the polymer backbone via thiol-ene click chemistry to impart desirable functionalities to the tubular scaffolds. Specifically, heparin was conjugated on the scaffolds in order to prevent thrombosis when implanted in situ. By controlling the amount of covalently attached heparin we were able to modulate the physical properties of the tubular scaffold, resulting in tunable wettability and degradation rate while retaining the porous and nanofibrous morphology. The scaffolds were successfully tested as rat abdominal aortic replacements. Patency and viability were confirmed through dynamic ultrasound and histological analysis of the regenerated tissue. The harvested tissue showed excellent vascular cellular infiltration, proliferation, and migration with laminar cellular arrangement. Furthermore, we achieved both complete reendothelialization of the vessel lumen and native-like media extracellular matrix. No signs of aneurysm or hyperplasia were observed after 3 months of vessel replacement. Taken together, we have developed an effective vascular graft able to generate small diameter blood vessels that can function in a rat model.


Assuntos
Heparina , Nanofibras , Animais , Biomimética , Prótese Vascular , Poliésteres , Ratos , Regeneração , Engenharia Tecidual , Tecidos Suporte
10.
Genomics ; 113(5): 3216-3223, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34051323

RESUMO

The European rabbit (Oryctolagus cuniculus) is important as a biomedical model given its unique features in immunity and metabolism. The current reference genome OryCun2.0 established with whole-genome shotgun sequencing was quite fragmented and had not been updated for ten years. In this work, we provided a new rabbit genome assembly UM_NZW_1.0 to improve OryCun2.0 by leveraging the contig lengths based on long-read sequencing and a wealth of available Illumina paired-end sequence data. UM_NZW_1.0 showed a remarkable increase of continuity compared with OryCun2.0, with 5 times longer contig N50 and approximately 75% gaps closed. Many of the closed gaps were overlapped with protein-coding genes or transcriptional features, resulting in an enhancement of gene annotations. In particular, UM_NZW_1.0 presented a more complete landscape of the MHC region and the IGH locus, therefore provided a valuable resource for future researches on rabbits.

11.
Cardiovasc Drugs Ther ; 35(3): 613-615, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33852094
12.
Cardiovasc Drugs Ther ; 35(3): 637-654, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33856594

RESUMO

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Genome-wide association studies (GWAS) are powerful epidemiological tools to find genes and variants associated with cardiovascular diseases while follow-up biological studies allow to better understand the etiology and mechanisms of disease and assign causality. Improved methodologies and reduced costs have allowed wider use of bulk and single-cell RNA sequencing, human-induced pluripotent stem cells, organoids, metabolomics, epigenomics, and novel animal models in conjunction with GWAS. In this review, we feature recent advancements relevant to cardiovascular diseases arising from the integration of genetic findings with multiple enabling technologies within multidisciplinary teams to highlight the solidifying transformative potential of this approach. Well-designed workflows integrating different platforms are greatly improving and accelerating the unraveling and understanding of complex disease processes while promoting an effective way to find better drug targets, improve drug design and repurposing, and provide insight towards a more personalized clinical practice.

13.
Hum Mol Genet ; 30(9): 836-842, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33693786

RESUMO

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (ß = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

15.
Cardiovasc Res ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538785

RESUMO

AIMS: Atherosclerosis is the dominant pathologic basis of many cardiovascular diseases. Large genome-wide association studies have identified that single nucleotide polymorphisms proximal to Krüppel-like factor 14 (KLF14), a member of the zinc finger family of transcription factors, are associated with higher cardiovascular risks. Macrophage dysfunction contributes to atherosclerosis development and has been recognized as a potential therapeutic target for treating many cardiovascular diseases. Herein, we address the biologic function of KLF14 in macrophages and its role during the development of atherosclerosis. METHODS AND RESULTS: KLF14 expression was markedly decreased in cholesterol-loaded foam cells, and overexpression of KLF14 significantly increased cholesterol efflux and inhibited the inflammatory response in macrophages. We generated myeloid cell-selective Klf14 knockout (Klf14LysM) mice in the ApoE-/- background for the atherosclerosis study. Klf14LysMApoE-/- and litter-mate control mice (Klf14fl/flApoE-/-) were placed on the Western Diet for 12 weeks to induce atherosclerosis. Macrophage Klf14 deficiency resulted in increased atherosclerosis development without affecting the plasma lipid profiles. Klf14-deficient peritoneal macrophages showed significantly reduced cholesterol efflux resulting in increased lipid accumulation and exacerbated inflammatory response. Mechanistically, KLF14 upregulates the expression of a key cholesterol efflux transporter, ABCA1 (ATP-binding cassette transporter A1), while suppresses the expression of several critical components of the inflammatory cascade. In macrophages, activation of KLF14 by its activator, perhexiline, a drug clinically used to treat angina, significantly inhibited the inflammatory response and increased cholesterol efflux in a KLF14- dependent manner in macrophages without triggering hepatic lipogenesis. CONCLUSIONS: This study provides insights into the anti-atherosclerotic effects of macrophage KLF14 through promoting cholesterol efflux and suppressing the inflammatory response. Activation of KLF14 may represent a potential new therapeutic approach to prevent or treat atherosclerosis. TRANSLATIONAL PERSPECTIVE: Here, using both gain- and loss-of-function strategies, we show that KLF14 regulates cholesterol efflux by regulating the expression of ABCA1 and inhibits inflammatory response in macrophages. These findings, along with our previous data, put activation of KLF14 forward as a prospective therapeutic target for atherosclerotic cardiovascular disease.

16.
Arterioscler Thromb Vasc Biol ; 41(4): e208-e223, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33535788
17.
Stem Cell Reports ; 16(3): 656-665, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33606990

RESUMO

Loss-of-function mutations in the forkhead box N1 (FOXN1) gene lead to nude severe combined immunodeficiency, a rare inherited syndrome characterized by athymia, severe T cell immunodeficiency, congenital alopecia, and nail dystrophy. We recently produced FOXN1 mutant nude rabbits (NuRabbits) by using CRISPR-Cas9. Here we report the establishment and maintenance of the NuRabbit colony. NuRabbits, like nude mice, are hairless, lack thymic development, and are immunodeficient. To demonstrate the functional applications of NuRabbits in biomedical research, we show that they can successfully serve as the recipient animals in xenotransplantation experiments using human induced pluripotent stem cells or tissue-engineered blood vessels. Our work presents the NuRabbit as a new member of the immunodeficient animal model family. The relatively large size and long lifespan of NuRabbits offer unique applications in regenerative medicine, cancer research, and the study of a variety of other human conditions, including immunodeficiency.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33558115

RESUMO

OBJECTIVE: The study objective was to determine the influence of allograft ischemic time on heart transplant outcomes among ABO donor organ types given limited prior reports of its survival impact. METHODS: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous and categoric variables were analyzed by parametric and nonparametric testing. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables. RESULTS: By comparing allograft ischemic time less than 4 hours (n = 6579) with 4 hours or more (n = 25,875), the hazard ratios for death at 15 years after prolonged ischemic time (≥4 hours) for blood types O, A, B, and AB were 1.106 (P < .001), 1.062 (P < .001), 1.059 (P = .062), and 1.114 (P = .221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for ischemic time 4 hours or more (hazard ratio, 1.164; P < .001). After propensity matching, O donor hearts continued to have worse survival if preserved for 4 hours or more (hazard ratio, 1.137, P = .008), but not if ischemic time was less than 4 hours (hazard ratio, 1.042, P = .113). In a matched group with 4 hours or more of ischemic time, patients receiving O donor organs were more likely to experience death from primary graft dysfunction (2.5% vs 1.7%, P = .052) and chronic allograft rejection (1.9% vs 1.1%, P = .021). No difference in death from primary graft dysfunction or chronic allograft rejection was seen with less than 4 hours of ischemic time (P > .150). CONCLUSIONS: Compared with non-O donor hearts, transplantation with O donor hearts with ischemic time 4 hours or more leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when anticipating extended cold ischemic times.

19.
EBioMedicine ; 63: 103207, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418500

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of death and a major cause of disability globally. Transcription factor EB (TFEB), as a member of the microphthalmia transcription factor (MITF) family, has been demonstrated to be a master regulator of autophagy and lysosomal biogenesis. Emerging studies suggest that TFEB regulates homeostasis in the cardiovascular system and shows beneficial effects on CVDs, including atherosclerosis, aortic aneurysm, postischemic angiogenesis, and cardiotoxicity, constituting a promising molecular target for the prevention and treatment of these diseases. Post-translational modifications regulate TFEB nuclear translocation and its transcriptional activity. Therapeutic strategies have been pursued to enhance TFEB activity and facilitate TFEB beneficial effects on CVDs. The elucidation of TFEB function and the precise underlying mechanisms will accelerate drug development and potential applications of TFEB drugs in the treatment of human diseases.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/metabolismo , Homeostase , Animais , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Suscetibilidade a Doenças , Descoberta de Drogas , Regulação da Expressão Gênica , Humanos , Lisossomos/metabolismo , Família Multigênica , Especificidade de Órgãos/genética
20.
JCI Insight ; 6(5)2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33507881

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening degenerative vascular disease. Endothelial cell (EC) dysfunction is implicated in AAA. Our group recently demonstrated that Krüppel-like factor 11 (KLF11) plays an essential role in maintaining vascular homeostasis, at least partially through inhibition of EC inflammatory activation. However, the functions of endothelial KLF11 in AAA remain unknown. Here we found that endothelial KLF11 expression was reduced in the ECs from human aneurysms and was time dependently decreased in the aneurysmal endothelium from both elastase- and Pcsk9/AngII-induced AAA mouse models. KLF11 deficiency in ECs markedly aggravated AAA formation, whereas EC-selective KLF11 overexpression markedly inhibited AAA formation. Mechanistically, KLF11 not only inhibited the EC inflammatory response but also diminished MMP9 expression and activity and reduced NADPH oxidase 2-mediated production of reactive oxygen species in ECs. In addition, KLF11-deficient ECs induced smooth muscle cell dedifferentiation and apoptosis. Overall, we established endothelial KLF11 as a potentially novel factor protecting against AAA and a potential target for intervention in aortic aneurysms.

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