Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 64
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Nat Genet ; 55(11): 1831-1842, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37845353

RESUMEN

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.


Asunto(s)
Aneurisma de la Aorta Abdominal , Estudio de Asociación del Genoma Completo , Humanos , Animales , Ratones , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Subtilisina , Proproteína Convertasas , Aneurisma de la Aorta Abdominal/genética
2.
Cell Rep ; 42(10): 113171, 2023 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-37768825

RESUMEN

Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques. Myeloid-specific Baf60a deletion compromised mitochondrial integrity and heightened adhesion, apoptosis, and plaque development. BAF60a preserves mitochondrial energy homeostasis under pro-atherogenic stimuli by retaining nuclear respiratory factor 1 (NRF1) accessibility at critical genes. Overexpression of BAF60a rescued mitochondrial dysfunction in an NRF1-dependent manner. This study illuminates the BAF60a-NRF1 axis as a mitochondrial function modulator in atherosclerosis, proposing the rejuvenation of perturbed chromatin remodeling machinery as a potential therapeutic target.


Asunto(s)
Aterosclerosis , Factores de Transcripción , Humanos , Aterosclerosis/genética , Ensamble y Desensamble de Cromatina , Regulación de la Expresión Génica , Homeostasis , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
JCI Insight ; 8(11)2023 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-37079380

RESUMEN

Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain-containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell-specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.


Asunto(s)
Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Ratones , Animales , Humanos , Músculo Liso Vascular/patología , Aneurisma de la Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Inflamación/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo
4.
J Clin Invest ; 132(21)2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36066968

RESUMEN

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both angiotensin II- (Ang II-) and elastase-induced AAA formation in mice, with a significant increase in elastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMCs resulted in loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex and suppressing VSMC inflammation by promoting a repressive chromatin state of NF-κB target genes as well as preventing VSMC apoptosis through transcriptional activation of KLF5-dependent B cell lymphoma 2 (BCL2) expression. Our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA.


Asunto(s)
Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Animales , Humanos , Ratones , Angiotensina II/metabolismo , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/prevención & control , Modelos Animales de Enfermedad , Epigénesis Genética , Homeostasis , Inflamación/patología , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo
5.
Nat Commun ; 13(1): 1757, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35365608

RESUMEN

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.


Asunto(s)
Microbioma Gastrointestinal , Aminoácidos Neutros , Animales , Cardiomegalia/metabolismo , Ácidos Grasos/metabolismo , Humanos , Ratones , Estudios Prospectivos , Valeratos
6.
Redox Biol ; 52: 102313, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35447412

RESUMEN

Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties. Glycine deficiency enhanced, while glycine supplementation attenuated, atherosclerosis development in apolipoprotein E-deficient (Apoe-/-) mice. DT-109 treatment showed the most significant atheroprotective effects and lowered atherosclerosis in the whole aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe-/- mice with established atherosclerosis, DT-109 treatment significantly reduced atherosclerosis and aortic superoxide independent of lipid-lowering effects. Targeted metabolomics and kinetics studies revealed that DT-109 induces glutathione formation in mononuclear cells. In bone marrow-derived macrophages (BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier subunit-deficient (Gclm-/-) mice in which glutathione biosynthesis is impaired. Metabolic flux and carbon tracing experiments revealed that glycine deficiency inhibits glutathione formation in BMDMs while glycine-based treatment induces de novo glutathione biosynthesis. Through a combination of studies in patients with CAD, in vivo studies using atherosclerotic mice and in vitro studies using macrophages, we demonstrated a causative role of glycine in atherosclerosis and identified glycine-based treatment as an approach to mitigate atherosclerosis through antioxidant effects mediated by induction of glutathione biosynthesis.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Glutamato-Cisteína Ligasa , Glutatión/metabolismo , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/metabolismo , Superóxidos
7.
Pharmacol Res ; 178: 106183, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35306139

RESUMEN

Most blood vessels are surrounded by perivascular adipose tissue (PVAT), which is a unique adipose tissue that plays critical roles in vascular physiology and pathophysiology. PVAT displays regional differences that impact vascular homeostasis. Angiotensin II (Ang II) is the main biologically active component of the renin-angiotensin-aldosterone system (RAAS), which has been extensively studied in vascular biology. However, the effects of Ang II on PVAT are less explored and remain to be elucidated. In this study, we systematically investigated the regional heterogeneity of three portions of aortic PVAT, i.e., ascending thoracic aortic PVAT (ATA-PVAT), descending thoracic aortic PVAT (DTA-PVAT) and abdominal aortic PVAT (AA-PVAT), and their responses to 7-day Ang II infusion using RNA sequencing. We found that AA-PVAT is clearly distinguished from both ATA-PVAT and DTA-PVAT, with significantly down-regulated oxidative phosphorylation and up-regulated inflammatory response pathways. Furthermore, AA-PVAT expresses lower levels of brown adipocyte marker genes, such as Ucp1, Cidea, Cox8b, Dio2 and Pgc1α, but expresses higher levels of proinflammatory genes, such as Ccl2, Il1ß and Tnfα, and components of the RAAS, including Agt, Ace and Agtr1a. Ang II infusion significantly down-regulated oxidative phosphorylation in all regions of aortic PVAT and significantly up-regulated inflammatory response specifically in ATA-PVAT and DTA-PVAT. Moreover, ATA-PVAT was most responsive to Ang II induced inflammation. We further used CDGSH iron-sulfur domain-containing protein 1 (a.k.a. mitoNEET) transgenic mice that exhibit enhanced brown adipose tissue (BAT)-like phenotype in aortic PVAT, as indicated by elevated expression levels of brown adipocyte marker genes, and found that the enhanced BAT-like phenotype of aortic PVAT could counterbalance Ang II induced inflammatory and oxidative effects.


Asunto(s)
Tejido Adiposo , Angiotensina II , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Aorta Torácica/metabolismo , Proteínas de Unión a Hierro/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Sistema Renina-Angiotensina , Análisis de Secuencia de ARN
8.
Cardiovasc Res ; 118(2): 475-488, 2022 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33538785

RESUMEN

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 it 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 myeloid 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.


Asunto(s)
Aorta/metabolismo , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Factores de Transcripción de Tipo Kruppel/deficiencia , Macrófagos/metabolismo , Placa Aterosclerótica , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Aorta/inmunología , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/patología , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Colesterol/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Células Hep G2 , Humanos , Interleucina-1beta/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Transducción de Señal , Células THP-1 , Factor de Transcripción ReIA/metabolismo
9.
iScience ; 24(11): 103196, 2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34746691

RESUMEN

The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice.

10.
Front Physiol ; 12: 699578, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34526909

RESUMEN

Increasing energy expenditure by promoting "browning" in adipose tissues is a promising strategy to prevent obesity and associated diabetes. To uncover potential targets of cold exposure, which induces energy expenditure, we performed phosphoproteomics profiling in brown adipose tissue of mice housed in mild cold environment at 16°C. We identified CDC2-like kinase 1 (CLK1) as one of the kinases that were significantly downregulated by mild cold exposure. In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22°C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays. We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPARγ), resulting in impaired adipose tissue browning and insulin sensitivity. These data suggest that CLK1 plays a critical role in controlling energy expenditure through the CLK1-THRAP3-PPARγ axis.

11.
Cell Rep ; 36(4): 109420, 2021 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-34320345

RESUMEN

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.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Terapia Molecular Dirigida , Oxalatos/metabolismo , Animales , Aorta/metabolismo , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Ácidos y Sales Biliares/metabolismo , Línea Celular , Quimiocina CCL5/metabolismo , Colesterol/metabolismo , Dependovirus/metabolismo , Femenino , Glicina/metabolismo , Homeostasis , Humanos , Inflamación/patología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Superóxidos/metabolismo , Transaminasas/deficiencia , Transaminasas/metabolismo
12.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34265237

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliales/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Sitios de Carácter Cuantitativo , Proteína 2 Similar al Factor de Transcripción 7/genética , Aorta/metabolismo , Aorta/patología , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Estudios de Casos y Controles , Caspasa 3/genética , Caspasa 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Células Endoteliales/patología , Regulación de la Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Intrones , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Mutación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
13.
Front Cell Dev Biol ; 9: 689469, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34095155

RESUMEN

Atherosclerosis is the leading cause of cardiovascular diseases, which is also the primary cause of mortality among diabetic patients. Endothelial cell (EC) dysfunction is a critical early step in the development of atherosclerosis and aggravated in the presence of concurrent diabetes. Although the heterogeneity of the organ-specific ECs has been systematically analyzed at the single-cell level in healthy conditions, their transcriptomic changes in diabetic atherosclerosis remain largely unexplored. Here, we carried out a single-cell RNA sequencing (scRNA-seq) study using EC-enriched single cells from mouse heart and aorta after 12 weeks feeding of a standard chow or a diabetogenic high-fat diet with cholesterol. We identified eight EC clusters, three of which expressed mesenchymal markers, indicative of an endothelial-to-mesenchymal transition (EndMT). Analyses of the marker genes, pathways, and biological functions revealed that ECs are highly heterogeneous and plastic both in normal and atherosclerotic conditions. The metabolic transcriptomic analysis further confirmed that EndMT-derived fibroblast-like cells are prominent in atherosclerosis, with diminished fatty acid oxidation and enhanced biological functions, including regulation of extracellular-matrix organization and apoptosis. In summary, our data characterized the phenotypic and metabolic heterogeneity of ECs in diabetes-associated atherogenesis at the single-cell level and paves the way for a deeper understanding of endothelial cell biology and EC-related cardiovascular diseases.

14.
iScience ; 24(4): 102363, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33898950

RESUMEN

AMP-activated protein kinase (AMPK) senses energy status and impacts energy-consuming events by initiating metabolism regulatory signals in cells. Accumulating evidences suggest a role of AMPK in mitosis regulation, but the mechanism of mitotic AMPK activation and function remains elusive. Here we report that AMPKα2, but not AMPKα1, is sequentially phosphorylated and activated by CDK1 and PLK1, which enables AMPKα2 to accurately guide chromosome segregation in mitosis. Phosphorylation at Thr485 by activated CDK1-Cyclin B1 brings the ST-stretch of AMPKα2 to the Polo box domain of PLK1 for subsequent Thr172 phosphorylation by PLK1. Inserting of the AMPKα2 ST-stretch into AMPKα1, which lacks the ST-stretch, can correct mitotic chromosome segregation defects in AMPKα2-depleted cells. These findings uncovered a specific signaling cascade integrating sequential phosphorylation by CDK1 and PLK1 of AMPKα2 with mitosis to maintain genomic stability, thus defining an isoform-specific AMPKα2 function, which will facilitate future research on energy sensing in mitosis.

15.
Cardiovasc Drugs Ther ; 35(3): 637-654, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33856594

RESUMEN

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.


Asunto(s)
Enfermedades Cardiovasculares/genética , Animales , Modelos Animales de Enfermedad , Epigenómica/métodos , Estudio de Asociación del Genoma Completo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Metabolómica/métodos , Organoides/metabolismo , ARN Citoplasmático Pequeño/genética , Análisis de Secuencia de ARN/métodos
16.
JCI Insight ; 6(5)2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33507881

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Abdominal/metabolismo , Proteínas Reguladoras de la Apoptosis/fisiología , Células Endoteliales , Proteínas Represoras/fisiología , Animales , Apoptosis , Desdiferenciación Celular , Línea Celular , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL
17.
Antioxid Redox Signal ; 34(9): 736-749, 2021 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32390459

RESUMEN

Significance: Perivascular adipose tissue (PVAT), which is present surrounding most blood vessels, from the aorta to the microvasculature of the dermis, is mainly composed of fat cells, fibroblasts, stem cells, mast cells, and nerve cells. Although the PVAT is objectively present, its physiological and pathological significance has long been ignored. Recent Advances: PVAT was considered as a supporting component of blood vessels and a protective cushion to the vessel wall from the neighboring tissues during relaxation and contraction. Nonetheless, further extensive research found that PVAT actively regulates blood vessel tone through PVAT-derived vasoactive factors, including both relaxing and contracting factors. In addition, PVAT contributes to atherosclerosis through paracrine secretion of a large number of bioactive factors such as adipokines and cytokines. Thereby, PVAT regulates the functions of blood vessels through various mechanisms operating directly on PVAT or on the underlying vessel layers, including vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Critical Issues: PVAT is a unique adipose tissue that plays an essential role in maintaining the vascular structure and regulating vascular function and homeostasis. This review focuses on recent updates on the various PVAT roles in hypertension and atherosclerosis. Future Directions: Future studies should further investigate the actual contribution of alterations in PVAT metabolism to the overall systemic outcomes of cardiovascular disease, which remains largely unknown. In addition, the messengers and underlying mechanisms responsible for the crosstalk between PVAT and ECs and VSMCs in the vascular wall should be systematically addressed, as well as the contributions of PVAT aging to vascular dysfunction.


Asunto(s)
Tejido Adiposo/metabolismo , Aterosclerosis/metabolismo , Hipertensión/metabolismo , Músculo Liso Vascular/metabolismo , Animales , Aterosclerosis/genética , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Hipertensión/genética , Hipertensión/patología , Células Musculares/metabolismo , Células Musculares/patología , Músculo Liso Vascular/patología , Comunicación Paracrina/genética
18.
Cardiovasc Res ; 117(5): 1402-1416, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32678909

RESUMEN

AIMS: The artery contains numerous cell types which contribute to multiple vascular diseases. However, the heterogeneity and cellular responses of these vascular cells during abdominal aortic aneurysm (AAA) progression have not been well characterized. METHODS AND RESULTS: Single-cell RNA sequencing was performed on the infrarenal abdominal aortas (IAAs) from C57BL/6J mice at Days 7 and 14 post-sham or peri-adventitial elastase-induced AAA. Unbiased clustering analysis of the transcriptional profiles from >4500 aortic cells identified 17 clusters representing nine-cell lineages, encompassing vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells, immune cells (macrophages, T cells, B cells, and dendritic cells), and two types of rare cells, including neural cells and erythrocyte cells. Seurat clustering analysis identified four smooth muscle cell (SMC) subpopulations and five monocyte/macrophage subpopulations, with distinct transcriptional profiles. During AAA progression, three major SMC subpopulations were proportionally decreased, whereas the small subpopulation was increased, accompanied with down-regulation of SMC contractile markers and up-regulation of pro-inflammatory genes. Another AAA-associated cellular response is immune cell expansion, particularly monocytes/macrophages. Elastase exposure induced significant expansion and activation of aortic resident macrophages, blood-derived monocytes and inflammatory macrophages. We also identified increased blood-derived reparative macrophages expressing anti-inflammatory cytokines suggesting that resolution of inflammation and vascular repair also persist during AAA progression. CONCLUSION: Our data identify AAA disease-relevant transcriptional signatures of vascular cells in the IAA. Furthermore, we characterize the heterogeneity and cellular responses of VSMCs and monocytes/macrophages during AAA progression, which provide insights into their function and the regulation of AAA onset and progression.


Asunto(s)
Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Linaje de la Célula , Perfilación de la Expresión Génica , RNA-Seq , Análisis de la Célula Individual , Transcriptoma , Animales , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Análisis por Conglomerados , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Macrófagos/patología , Ratones Endogámicos C57BL , Monocitos/metabolismo , Monocitos/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Elastasa Pancreática , Fenotipo
19.
Atherosclerosis ; 316: 32-40, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33296791

RESUMEN

BACKGROUND AND AIMS: Apolipoprotein A-II (apoAII) is the second major apolipoprotein of the high-density lipoprotein (HDL) particle, after apoAI. Unlike apoAI, the biological and physiological functions of apoAII are unclear. We aimed to gain insight into the specific roles of apoAII in lipoprotein metabolism and atherosclerosis using a novel rabbit model. METHODS: Wild-type (WT) rabbits are naturally deficient in apoAII, thus their HDL contains only apoAI. Using TALEN technology, we replaced the endogenous apoAI in rabbits through knock-in (KI) of human apoAII. The newly generated apoAII KI rabbits were used to study the specific function of apoAII, independent of apoAI. RESULTS: ApoAII KI rabbits expressed exclusively apoAII without apoAI, as confirmed by RT-PCR and Western blotting. On a standard diet, the KI rabbits exhibited lower plasma triglycerides (TG, 52%, p < 0.01) due to accelerated clearance of TG-rich particles and higher lipoprotein lipase activity than the WT littermates. ApoAII KI rabbits also had higher plasma HDL-C (28%, p < 0.05) and their HDL was rich in apoE, apoAIV, and apoAV. When fed a cholesterol-rich diet for 16 weeks, apoAII KI rabbits were resistant to diet-induced hypertriglyceridemia and developed significantly less aortic atherosclerosis compared to WT rabbits. HDL isolated from rabbits with apoAII KI had similar cholesterol efflux capacity and anti-inflammatory effects as HDL isolated from the WT rabbits. CONCLUSIONS: ApoAII KI rabbits developed less atherosclerosis than WT rabbits, possibly through increased plasma HDL-C, reduced TG and atherogenic lipoproteins. These results suggest that apoAII may serve as a potential target for the treatment of atherosclerosis.


Asunto(s)
Apolipoproteína A-II , Aterosclerosis , Animales , Apolipoproteína A-I/genética , Aterosclerosis/genética , Aterosclerosis/prevención & control , Colesterol , Humanos , Lipoproteínas HDL , Conejos
20.
Arterioscler Thromb Vasc Biol ; 41(2): 783-795, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33297755

RESUMEN

OBJECTIVE: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis. However, the role of endothelial TFEB in metabolism remains to be explored. In this study, we sought to investigate the role of endothelial TFEB in glucose metabolism and underlying molecular mechanisms. Approach and Results: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout and EC-selective TFEB transgenic mice fed a high-fat diet. EC-selective TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-selective TFEB transgenic mice showed improved glucose tolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts Akt (AKT serine/threonine kinase) signaling. Adenovirus-mediated overexpression of TFEB consistently activates Akt and significantly increases glucose uptake in ECs. Mechanistically, TFEB upregulates IRS1 and IRS2 (insulin receptor substrate 1 and 2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495, and miR-548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-selective TFEB knockout mice and consistently improved in EC-selective TFEB transgenic mice on high-fat diet. CONCLUSIONS: Our data revealed a critical role of TFEB in endothelial metabolism and suggest that TFEB constitutes a potential molecular target for the treatment of vascular and metabolic diseases.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Glucemia/metabolismo , Células Endoteliales/metabolismo , Intolerancia a la Glucosa/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Tejido Adiposo/metabolismo , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Glucemia/efectos de los fármacos , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Femenino , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/genética , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Insulina/farmacología , Proteínas Sustrato del Receptor de Insulina/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...