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2.
Atherosclerosis ; 327: 49-58, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34038763

RESUMO

BACKGROUND AND AIMS: Preclinical data suggest that the ageing-induced miR-34a regulates vascular senescence. Herein we sought to assess whether the miR-34 family members miR-34a, miR-34b and miR-34c are involved in human arterial disease. METHODS: Expression levels of miR-34a/b/c were quantified by TaqMan assay in peripheral blood mononuclear cells (PBMCs) derived from a consecutive cohort of 221 subjects who underwent cardiovascular risk assessment and thorough vascular examination for aortic stiffness and extent of arterial atherosclerosis. RESULTS: High miR-34a was independently associated with the presence of CAD [OR (95%C.I.): 3.87 (1.56-9.56); p = 0.003] and high miR-34c with the number of diseased arterial beds [OR (95%C.I.): 1.88 (1.034-3.41); p = 0.038], while concurrent high expression of miR-34-a/c or all three miR-34a/b/c was associated with aortic stiffening (miR-34a/c: p = 0.022; miR-34a/b/c: p = 0.041) and with the extent of atherosclerosis [OR (95%C.I.) for number of coronary arteries [miR-34a/c: 3.29 (1.085-9.95); miR-34a/b/c: 6.06 (1.74-21.2)] and number of diseased arterial beds [miR-34a/c: 3.51 (1.45-8.52); miR-34a/b/c: 2.89 (1.05-7.92)] after controlling for possible confounders (p < 0.05 for all). Mechanistically, the increased levels of miR-34a or miR-34c were inversely associated with expression of SIRT1 or JAG1, NOTCH2, CTNNB1 and ATF1, respectively. The association of miR-34a/c or miR-34a/b/c with CAD was mainly mediated through SIRT1 and to a lesser extent through JAG1 as revealed by generalized structural equation modeling. Leukocyte-specific ablation of miR-34a/b/c ameliorates atherosclerotic plaque development and increases Sirt1 and Jag1 expression in an atherosclerosis mouse model confirming the human findings. CONCLUSIONS: The present study reveals the clinical significance of the additive role of miR-34a/b/c in vascular ageing and atherosclerotic vascular disease.


Assuntos
Envelhecimento , Aterosclerose , MicroRNAs , Humanos , Proteína Jagged-1 , Leucócitos Mononucleares , Sirtuína 1
5.
Thromb Haemost ; 121(5): 650-658, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33202443

RESUMO

BACKGROUND: Accumulating evidence suggests that circulating amyloidß 1-40 (Αß1-40), a proatherogenic aging peptide, may serve as a novel biomarker in cardiovascular disease (CVD). We aimed to explore the role of plasma Αß1-40 and its patterns of change over time in atherosclerosis progression in postmenopausal women, a population with substantial unrecognized CVD risk beyond traditional risk factors (TRFs). METHODS: In this prospective study, Αß1-40 was measured in plasma by enzyme-linked immunosorbent assay and atherosclerosis was assessed using carotid high-resolution ultrasonography at baseline and after a median follow-up of 28.2 months in 152 postmenopausal women without history or symptoms of CVD. RESULTS: At baseline, high Αß1-40 was independently associated with higher carotid bulb intima-media thickness (cbIMT) and the sum of maximal wall thickness in all carotid sites (sumWT) (p < 0.05). Αß1-40 levels increased over time and were associated with decreasing renal function (p < 0.05 for both). Women with a pattern of increasing or persistently high Αß1-40 levels presented accelerated progression of cbIMT and maximum carotid wall thickness and sumWT (p < 0.05 for all) after adjustment for baseline Αß1-40 levels, TRFs, and renal function. CONCLUSION: In postmenopausal women, a pattern of increasing or persistently high Αß1-40 was associated with the rate of progression of subclinical atherosclerosis irrespective of its baseline levels. These findings provide novel insights into a link between Αß1-40 and atherosclerosis progression in menopause and warrant further research to clarify the clinical value of monitoring its circulating levels as an atherosclerosis biomarker in women without clinically overt CVD.

7.
Aging Cell ; 19(10): e13249, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32996233

RESUMO

A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-ß3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.


Assuntos
Senescência Celular/fisiologia , Traumatismo por Reperfusão/metabolismo , Feminino , Humanos , Masculino
8.
J Am Coll Cardiol ; 75(8): 952-967, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32130931

RESUMO

Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer's disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aß) peptides may function as a link among aging, CVD, and AD. Aging-related vascular and cardiac deposition of Αß induces tissue inflammation and organ dysfunction, both important components of the Alzheimer's disease amyloid hypothesis. In this review, the authors describe the determinants of Aß metabolism, summarize the effects of Aß on atherothrombosis and cardiac dysfunction, discuss the clinical value of Αß1-40 in CVD prognosis and patient risk stratification, and present the therapeutic interventions that may alter Aß metabolism in humans.


Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Cardiovasculares/metabolismo , Doença de Alzheimer/etiologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Humanos , Mortalidade , Medição de Risco
10.
Circ Res ; 126(2): 243-257, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31805812

RESUMO

RATIONALE: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.


Assuntos
Malformações Arteriovenosas/metabolismo , Endoglina/genética , Endotélio Vascular/metabolismo , Insuficiência Cardíaca/etiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Pressão Sanguínea , Proliferação de Células , Endoglina/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
JCI Insight ; 52019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30835717

RESUMO

Sarcomeric disarray is a hallmark of gene mutations in patients with Hypertrophic Cardiomyopathy (HCM). However, it is unknown when detrimental sarcomeric changes first occur and whether they originate in the developing embryonic heart. Furthermore, Rho Kinase (ROCK) is a serine threonine protein kinase that is critical for regulating the function of several sarcomeric proteins and therefore, our aim was to determine if disruption of ROCK signalling during the earliest stages of heart development would disrupt the integrity of sarcomeres altering heart development and function. Using a mouse model in which the function of ROCK is specifically disrupted in embryonic cardiomyocytes we demonstrate a progressive cardiomyopathy that first appeared as sarcomeric disarray during cardiogenesis. This led to abnormalities in the structure of embryonic ventricular wall and compensatory cardiomyocyte hypertrophy during foetal development. This sarcomeric disruption and hypertrophy persisted throughout adult life, triggering left ventricular concentric hypertrophy with systolic dysfunction, and re-activation of foetal gene expression and cardiac fibrosis, all typical features of HCM. Taken together, our findings establish a novel mechanism for the developmental origin of the sarcomeric phenotype of HCM and suggest that variants in the ROCK genes or disruption of ROCK signalling could, in part, contribute to its pathogenesis.


Assuntos
Cardiomiopatia Hipertrófica/genética , Ventrículos do Coração/patologia , Sarcômeros/patologia , Quinases Associadas a rho/genética , Animais , Cardiomiopatia Hipertrófica/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Ventrículos do Coração/citologia , Ventrículos do Coração/embriologia , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/patologia , Sarcômeros/metabolismo , Quinases Associadas a rho/metabolismo
12.
J Mol Cell Cardiol ; 129: 272-280, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30880252

RESUMO

Cardiovascular disease (CVD) remains the leading cause of death in the Western world. Despite advances in the prevention and in the management of CVD, the role of RNA epigenetics in the cardiovascular system has been until recently unexplored. The rapidly expanding research field of RNA modifications has introduced a novel layer of gene regulation in mammalian cells. RNA modifications may control all aspects of RNA metabolism, and their study reveals previously unrecognized regulatory pathways that may determine gene expression at a post-transcriptional level. Understanding the role of RNA modifications in CVD may lead towards a better understanding of disease mechanisms and the development of novel biomarkers or therapeutic strategies. In this review, we highlight the most recent and major reports in the field of RNA methylation and adenosine to inosine RNA editing related to the cardiovascular field and we discuss how this breakthrough will advance the field of precision medicine.


Assuntos
Doenças Cardiovasculares/genética , Epigênese Genética , RNA/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Metilação de DNA/genética , Humanos , RNA/metabolismo , Edição de RNA/genética
13.
Aging Cell ; 18(3): e12945, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30920115

RESUMO

Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age-related pathologies. However, the role of senescence in recovery following MI has not been investigated. In this study, we demonstrate that treatment of aged mice with the senolytic drug, navitoclax, eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice. Importantly, clearance of senescent cells improved myocardial remodelling and diastolic function as well as overall survival following MI. These data provide proof-of-concept evidence that senescent cells are major contributors to impaired function and increased mortality following MI and that senolytics are a potential new therapeutic avenue for MI.


Assuntos
Envelhecimento/efeitos dos fármacos , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Sulfonamidas/farmacologia , Doença Aguda , Compostos de Anilina/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Sulfonamidas/administração & dosagem
14.
EMBO J ; 38(5)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30737259

RESUMO

Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a, and results in a non-canonical senescence-associated secretory phenotype, which is pro-fibrotic and pro-hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age-related myocardial dysfunction and in the wider setting to ageing in post-mitotic tissues.


Assuntos
Cardiomegalia/patologia , Senescência Celular , Dano ao DNA , Fibrose/patologia , Mitose , Miócitos Cardíacos/patologia , Encurtamento do Telômero , Envelhecimento , Animais , Cardiomegalia/etiologia , Feminino , Fibrose/etiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monoaminoxidase/fisiologia , Miócitos Cardíacos/metabolismo , Fenótipo , RNA/fisiologia , Ratos Sprague-Dawley , Telomerase/fisiologia
15.
Circulation ; 138(23): 2698-2712, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30571259

RESUMO

BACKGROUND: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. METHODS: We took advantage of Acvrl1+/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1+/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. RESULTS: Acvrl1+/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1+/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1+/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1+/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1+/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1+/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1+/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1+/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. CONCLUSIONS: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.


Assuntos
Telangiectasia Hemorrágica Hereditária/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptores de Ativinas Tipo I/genética , Receptores de Activinas Tipo II , Adulto , Animais , Anticorpos/administração & dosagem , Anticorpos/imunologia , Malformações Arteriovenosas/etiologia , Modelos Animais de Doenças , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Mycoplasma pulmonis/fisiologia , Neovascularização Fisiológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Vasos Retinianos/fisiologia , Transdução de Sinais , Pele/patologia , Telangiectasia Hemorrágica Hereditária/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia
16.
Dis Model Mech ; 11(9)2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30108051

RESUMO

Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1 (HHT1), characterized by arteriovenous malformations (AVMs) in different organs. These vascular lesions derive from abnormal processes of angiogenesis, whereby aberrant vascular remodeling leads to focal loss of capillaries. Current treatments for HHT1 include antiangiogenic therapies. Interestingly, a circulating form of endoglin (also known as soluble endoglin, sEng), proteolytically released from the membrane-bound protein and displaying antiangiogenic activity, has been described in several endothelial-related pathological conditions. Using human and mouse endothelial cells, we find that sEng downregulates several pro-angiogenic and pro-migratory proteins involved in angiogenesis. However, this effect is much reduced in endothelial cells that lack endogenous transmembrane endoglin, suggesting that the antiangiogenic activity of sEng is dependent on the presence of endogenous transmembrane endoglin protein. In fact, sEng partially restores the phenotype of endoglin-silenced endothelial cells to that of normal endothelial cells. Moreover, using an established neonatal retinal model of HHT1 with depleted endoglin in the vascular endothelium, sEng treatment decreases the number of AVMs and has a normalizing effect on the vascular phenotype with respect to vessel branching, vascular density and migration of the vascular plexus towards the retinal periphery. Taken together, these data show that circulating sEng can influence vascular development and AVMs by modulating angiogenesis, and that its effect on endothelial cells depends on the expression of endogenous endoglin.This article has an associated First Person interview with the first author of the paper.


Assuntos
Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Endoglina/metabolismo , Regulação da Expressão Gênica , Neovascularização Patológica/genética , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/patologia , Animais , Biomarcadores/metabolismo , Movimento Celular , Modelos Animais de Doenças , Endoglina/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Pulmão/patologia , Camundongos Knockout , Modelos Biológicos , Retina/patologia , Solubilidade , Cicatrização
17.
Stem Cell Reports ; 8(5): 1287-1298, 2017 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-28494939

RESUMO

Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor ß (TGFß) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we therefore hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. Importantly, BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation.


Assuntos
Endoglina/metabolismo , Miocárdio/citologia , Neovascularização Fisiológica , Comunicação Parácrina , Células-Tronco/fisiologia , Animais , Células Cultivadas , Endoglina/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/metabolismo
18.
Int J Cardiol Heart Vasc ; 11: 29-34, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27882341

RESUMO

BACKGROUND: Mice are frequently used in research to examine outcomes of myocardial infarction (MI) and to investigate therapeutic interventions at an early pre-clinical stage. The MI model is generated by surgically occluding a major coronary artery, but natural variation in murine coronary anatomy can generate variable outcomes that will inevitably affect the accuracy of such investigations. The aim of this study was to use MRI to derive the most sensitive early variable that could be used to predict subsequent adverse cardiac remodelling in a male mouse model of MI. METHODS: Using a longitudinal study design, heart structure and function were evaluated using cardiac MRI at one week following surgical MI to generate the early measurements and again at four weeks, when the scar had matured. The primary variables measured at week one were left ventricular volumes at end systole (LV-ESV) and at end diastole (LV-EDV), infarct size, LV-cardiac mass, and ejection fraction (EF). RESULTS: Univariate and multiple regression analyses showed that LV-ESV at one week following MI could be used to accurately predict various parameters of adverse LV remodelling at four weeks post-MI. However, the highest correlation was between LV-ESV at one week following MI and LV-EDV at four weeks (r = 0.99; p < 0.0001), making LV-ESV at one week a valuable predictor variable of future adverse ventricular remodelling after MI. CONCLUSION: Using MRI to determine LV-ESV at an early stage following MI enables a more robust analysis of potential therapeutic interventions to ameliorate adverse cardiac remodelling.

19.
Clin Sci (Lond) ; 129(8): 687-98, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26201020

RESUMO

During sepsis, endothelial barrier dysfunction contributes to cardiovascular failure, mainly through the release of oxidative metabolites by penetrant leukocytes. We reported the non-muscular isoform of myosin light chain kinase (nmMLCK) playing a pivotal role in endotoxin shock injury associated with oxidative and nitrative stresses, and vascular hyporeactivity. The present study was aimed at understanding the molecular mechanism of lipopolysaccharide (LPS)-induced vascular alterations as well as studying a probable functional association of nmMLCK with nuclear factor κ-light-chain enhancer of activated B cells (NF-κB). Aortic rings from mice were exposed in vitro to LPS and, then, vascular reactivity was measured. Human aortic endothelial cells (HAoECs) were incubated with LPS, and interaction of nmMLCK with NF-κB was analysed. We provide evidence that nmMLCK deletion prevents vascular hyporeactivity induced by in vitro LPS treatment but not endothelial dysfunction in the aorta. Deletion of nmMLCK inhibits LPS-induced NF-κB activation and increases nitric oxide (NO) release via induction of inducible NO synthase (iNOS) within the vascular wall. Also, removal of endothelium prevented both NF-κB and iNOS expression in aortic rings. Among the proinflammatory factors released by LPS-treated endothelial cells, interleukin-6 accounts for the induction of iNOS on smooth muscle cells in response to LPS. Of particular interest is the demonstration that, in HAoECs, LPS-induced NF-κB activation occurs via increased MLCK activity sensitive to the MLCK inhibitor, ML-7, and physical interactions between nmMLCK and NF-κB. We report for the first time on NF-κB as a novel partner of nmMLCK within endothelial cells. The present study demonstrates a pivotal role of nmMLCK in vascular inflammatory pathologies.


Assuntos
Endotélio Vascular/enzimologia , Quinase de Cadeia Leve de Miosina/metabolismo , NF-kappa B/metabolismo , Sepse/enzimologia , Animais , Aorta/enzimologia , Células Cultivadas , Endotélio Vascular/fisiopatologia , Humanos , Técnicas In Vitro , Lipopolissacarídeos , Masculino , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Sepse/fisiopatologia
20.
Front Genet ; 6: 25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25741358

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by a multi-systemic vascular dysplasia and hemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). Both genes are associated with TGFß/BMP signaling, and loss of function mutations in the co-receptor ENG are causal in HHT1, while HHT2 is associated with mutations in the signaling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis and heart development. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the future.

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