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1.
Metabolism ; 114: 154390, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039407

RESUMO

BACKGROUND: Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K+ channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D. METHODOLOGY: Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca2+ in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging. MAIN FINDINGS: Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 µM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca2+ elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca2+ release by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid. CONCLUSIONS: Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca2+ mobilization.


Assuntos
Artérias/metabolismo , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Acetilcolina/farmacologia , Animais , Artérias/efeitos dos fármacos , Bradicinina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Músculo Esquelético/irrigação sanguínea , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
2.
Nat Commun ; 11(1): 5303, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082339

RESUMO

The L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Artérias/metabolismo , Canais de Cálcio Tipo L/metabolismo , Proteínas de Ancoragem à Quinase A/genética , Animais , Canais de Cálcio Tipo L/genética , AMP Cíclico/metabolismo , Glucose/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Camundongos Knockout , Células Musculares/metabolismo , Ligação Proteica
3.
Rev Med Suisse ; 16(711): 1970-1973, 2020 Oct 21.
Artigo em Francês | MEDLINE | ID: mdl-33085252

RESUMO

Arterial punctures are frequent procedures performed by hospital internists. It provides crucial information on acid-base status, oxygenation and the quality of gas exchanges. Nevertheless, this intervention is often painful and carries potential risks. This review aims to summarize the literature about this subject and to address the accuracy of the results obtained by point-of-care analysis.


Assuntos
Artérias/metabolismo , Gasometria/métodos , Punções/efeitos adversos , Humanos , Dor/etiologia , Sistemas Automatizados de Assistência Junto ao Leito
4.
Am J Physiol Renal Physiol ; 319(4): F618-F623, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830534

RESUMO

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3-5 has been shown to be as high as 79% (20). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease (6, 20, 50, 55). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH)2 vitamin D decrease. These imbalances have been linked to the development of vascular calcification. More recently, additional factors have been found to play a role in vascular calcification. Matrix G1a protein (MGP) in its carboxylated form (cMGP) is a potent inhibitor of vascular calcification. Importantly, carboxylation of MGP is dependent on the cofactor vitamin K. In patients with CKD, vitamin K deficiency is prevalent and is exacerbated by warfarin, which is frequently used for anticoagulation. Insufficient bioavailability of vitamin K reduces the amount of cMGP available, and, therefore, it may lead to increased risk of vascular calcification. In vitro studies have shown that in the setting of a high-phosphate environment and vitamin K antagonism, human aortic valve interstitial cells become calcified. In this article, we discuss the pathophysiological consequence of vitamin K deficiency in the setting of altered mineral and bone metabolism, its prevalence, and clinical implications in patients with CKD.


Assuntos
Artérias/metabolismo , Doença Iatrogênica , Diálise Renal , Insuficiência Renal Crônica/terapia , Calcificação Vascular/metabolismo , Deficiência de Vitamina K/metabolismo , Vitamina K/metabolismo , Animais , Anticoagulantes/efeitos adversos , Artérias/fisiopatologia , Suplementos Nutricionais , Humanos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Transdução de Sinais , Calcificação Vascular/epidemiologia , Calcificação Vascular/fisiopatologia , Calcificação Vascular/prevenção & controle , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico , Deficiência de Vitamina K/tratamento farmacológico , Deficiência de Vitamina K/epidemiologia , Deficiência de Vitamina K/fisiopatologia , Varfarina/efeitos adversos
5.
Am J Physiol Heart Circ Physiol ; 319(4): H835-H846, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795179

RESUMO

Analyses of individual atherosclerotic plaques are mostly descriptive, relying, for example, on histological classification by spectral analysis of ultrasound waves or staining and observing particular cellular components. Such passive methods have proved useful for characterizing the structure and vulnerability of plaques but have little quantitative predictive power. Our aim is to introduce and discuss a computational framework to provide insight to clinicians and help them visualize internal plaque dynamics. We use partial differential equations (PDEs) with macrophages, necrotic cells, oxidized lipids, oxygen concentration, and platelet-derived growth factor (PDGF) as primary variables coupled to a biomechanical model to describe vessel growth. The model is deterministic, providing mechanical, morphological, and histological characteristics of an atherosclerotic vessel at any desired future time point. We use our model to create computer-generated animations of a plaque evolution that are in qualitative agreement with published serial ultrasound images and hypothesize possible atherogenic mechanisms. A systems biology model consisting of five differential equations is able to capture the morphology of necrotic cores residing within vulnerable atherosclerotic plaque. In the context of the model, the distribution of oxidized low-density lipoprotein (Ox-LDL) particles, endothelial inflammation, plaque oxygenation (via the presence of vasa vasora), and intimal oxygenation are four important factors that drive changes in core morphology.NEW & NOTEWORTHY In this article, we propose a quantitative framework to describe the evolution of atherosclerotic plaque. We use partial differential equations (PDEs) with macrophages, necrotic cells, oxidized lipids, oxygen concentration, and PDGF as primary variables coupled to a biomechanical model to describe vessel growth. A feature of our method is that it outputs color-coded vessel sections corresponding to regions of the plaque that are necrotic and fibrous, qualitatively similar to images generated by enhanced intravascular ultrasound.


Assuntos
Artérias/patologia , Aterosclerose/patologia , Simulação por Computador , Modelos Cardiovasculares , Placa Aterosclerótica , Biologia de Sistemas , Animais , Artérias/metabolismo , Aterosclerose/metabolismo , Difusão , Progressão da Doença , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Mediadores da Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Necrose , Oxigênio/metabolismo
6.
Vascul Pharmacol ; 133-134: 106779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32814163

RESUMO

Atherosclerosis is a very common macrovascular complication in type 2 diabetes mellitus, and cardiovascular disease is the primary cause of death in diabetes patients. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are a newly identified class of drugs targeting the renal proximal tubules to increase glucose excretion. Large-scale clinical trials have confirmed the cardiovascular protective effects of SGLT inhibitors in patients with diabetes diagnosed with or at a higher risk of atherosclerotic cardiovascular disease. In addition to its direct effect on glycemic control, the function of SGLT-2i in the alleviation of volume load, renal protection, and reduction of inflammation plays an essential role in its therapeutic effect on atherosclerosis. SGLT-2i are known to decrease the levels of inflammatory factors in circulation and in arteries in situ, inhibit foam cell formation and macrophage infiltration, and sustain plaque stability, ultimately blocking the development and progression of atherosclerosis.


Assuntos
Anti-Infecciosos/uso terapêutico , Artérias/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Anti-Infecciosos/efeitos adversos , Artérias/metabolismo , Artérias/patologia , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Placa Aterosclerótica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
7.
Cardiovasc Pathol ; 49: 107259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692664

RESUMO

Perivascular adipose tissue (PVAT) is a fat tissue deposit that encircles the vasculature. PVAT is traditionally known to protect the vasculature from external stimuli that could cause biological stress. In addition to the protective role of PVAT, it secretes certain biologically active substances known as adipokines that induce paracrine effects on proximate blood vessels. These adipokines influence vascular tones. There are different types of PVAT and they are phenotypically and functionally distinct. These are the white and brown PVATs. Under certain conditions, white PVAT could undergo phenotypic switch to attain a brown PVAT-like phenotype. This type of PVAT is referred to as Beige PVAT. The morphology of adipose tissue is influenced by species, age, and sex. These factors play significant roles in adipose tissue mass, functionality, paracrine activity, and predisposition to vascular diseases. The difficulty that is currently experienced in extrapolating animal models to human physiology could be traceable to these factors. Up till now, the involvement of PVAT in the development of vascular pathology is still not well understood. Brown and white PVAT contribute differently to vascular pathology. Thus, the PVAT could be a therapeutic target in curbing certain vascular diseases. In this review, knowledge would be updated on the multifaceted involvement of PVAT in vascular pathology and also explore its vascular therapeutic potential.


Assuntos
Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Artérias/patologia , Doenças Vasculares/patologia , Adipocinas/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/fisiopatologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Artérias/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Hemodinâmica , Humanos , Mediadores da Inflamação/metabolismo , Comunicação Parácrina , Transdução de Sinais , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia
8.
Arterioscler Thromb Vasc Biol ; 40(9): 2002-2017, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698685

RESUMO

Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.


Assuntos
Artérias/metabolismo , Aterosclerose/metabolismo , RNA Longo não Codificante/metabolismo , Lesões do Sistema Vascular/metabolismo , Animais , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/terapia , Constrição Patológica , Epigênese Genética , Marcadores Genéticos , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Placa Aterosclerótica , RNA Longo não Codificante/genética , RNA Longo não Codificante/uso terapêutico , Terapêutica com RNAi , Transdução de Sinais , Remodelação Vascular , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia , Lesões do Sistema Vascular/terapia
9.
Am J Physiol Heart Circ Physiol ; 319(1): H203-H212, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502374

RESUMO

High-altitude (>2,500 m) residence increases the incidence of intrauterine growth restriction (IUGR) due, in part, to reduced uterine artery blood flow and impaired myometrial artery (MA) vasodilator response. A role for the AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR is suggested by genomic and transcriptomic studies in humans and functional studies in mice. AMPK is a hypoxia-sensitive metabolic sensor with vasodilatory properties. Here we hypothesized that AMPK-dependent vasodilation was increased in MAs from high versus low-altitude (<1,700 m) Colorado women with appropriate for gestational age (AGA) pregnancies and reduced in IUGR pregnancies regardless of altitude. Vasoreactivity studies showed that, in AGA pregnancies, MAs from high-altitude women were more sensitive to vasodilation by activation of AMPK with A769662 due chiefly to increased endothelial nitric oxide production, whereas MA responses to AMPK activation in the low-altitude women were endothelium independent. MAs from IUGR compared with AGA pregnancies had blunted vasodilator responses to acetylcholine at high altitude. We concluded that 1) blunted vasodilator responses in IUGR pregnancies confirm the importance of MA vasodilation for normal fetal growth and 2) the increased sensitivity to AMPK activation in AGA pregnancies at high altitude suggests that AMPK activation helped maintain MA vasodilation and fetal growth. These results highlight a novel mechanism for vasodilation of MAs under conditions of chronic hypoxia and suggest that AMPK activation could provide a therapy for increasing uteroplacental blood flow and improving fetal growth in IUGR pregnancies.NEW & NOTEWORTHY Intrauterine growth restriction (IUGR) impairs infant well- being and increases susceptibility to later-in-life diseases for mother and child. Our study reveals a novel role for AMPK in vasodilating the myometrial artery (MA) from women residing at high altitude (>2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any altitude.


Assuntos
Doença da Altitude/metabolismo , Artérias/metabolismo , Retardo do Crescimento Fetal/metabolismo , Miométrio/irrigação sanguínea , Proteínas Quinases/metabolismo , Vasodilatação , Adulto , Doença da Altitude/fisiopatologia , Artérias/efeitos dos fármacos , Artérias/fisiopatologia , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Óxido Nítrico/metabolismo , Gravidez , Pironas/farmacologia , Tiofenos/farmacologia
10.
J Vasc Res ; 57(4): 185-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526735

RESUMO

Information on the function of transient receptor potential vanilloid 1 (TRPV1) in arteriogenesis is limited. We aimed to verify whether TRPV1 is involved in collateral vessel growth in rat hind limbs and elucidate the possible subcellular action mechanisms. Adult Sprague Dawley rats were chosen to establish the hind limb ischemic model and treatment with capsaicin. Angiographies were performed, and tissue was isolated for immunohistochemistry. In vitro, rat aortic endothelial cells (RAECs) were treated with capsaicin and antagonist capsazepine. The RAEC proliferation was determined, and the protein and mRNA levels of Ca2+-dependent transcription factors were assessed. In vivo, the collateral vessels exhibited positive outward remodeling characterized by enhanced inflammatory cell/macrophage accumulation in the adventitia and activated cell proliferation in all layers of the vascular wall and elevated endothelial NO synthetase expression in the rats with hind limb ligation. In RAECs, TRPV1 activation-induced Ca2+-dependent transcriptional factors, nuclear factor of activated T cells 1, calsenilin and myocyte enhancer factor 2C increase, and augmented RAEC proliferation could be a subcellular mechanism for TRPV1 in endothelial cells and ultimately contribute to collateral vessel growth. TRPV1, a novel candidate, positively regulates arteriogenesis, meriting further studies to unravel the potential therapeutic target leading to improved collateral vessel growth for treating ischemic diseases.


Assuntos
Indutores da Angiogênese/farmacologia , Artérias/efeitos dos fármacos , Capsaicina/farmacologia , Circulação Colateral/efeitos dos fármacos , Isquemia/tratamento farmacológico , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Canais de Cátion TRPV/agonistas , Animais , Artérias/metabolismo , Artérias/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Membro Posterior , Isquemia/metabolismo , Isquemia/fisiopatologia , Proteínas Interatuantes com Canais de Kv/metabolismo , Fatores de Transcrição MEF2/metabolismo , Fatores de Transcrição NFATC/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Transdução de Sinais , Canais de Cátion TRPV/metabolismo
11.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L289-L293, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32491950

RESUMO

When using a new noninvasive method for measuring the efficiency of pulmonary gas exchange, a key measurement is the oxygen deficit, defined as the difference between the end-tidal alveolar Po2 and the calculated arterial Po2. The end-tidal Po2 is measured using a rapid gas analyzer, and the arterial Po2 is derived from pulse oximetry after allowing for the effect of the Pco2 on the oxygen affinity of hemoglobin. In the present report we show that the values of end-tidal Po2 and Pco2 are highly reproducible, providing a solid foundation for the measurement of the oxygen deficit. We compare the oxygen deficit with the classical ideal alveolar-arterial Po2 difference (A-aDO2) as originally proposed by Riley, and now extensively used in clinical practice. This assumes Riley's criteria for ideal alveolar gas, namely no ventilation-perfusion inequality, the same Pco2 as arterial blood, and the same respiratory exchange ratio as the whole lung. It transpires that, in normal subjects, the end-tidal Po2 is essentially the same as the ideal value. This conclusion is consistent with the very small oxygen deficit that we have reported in young normal subjects, the significantly higher values seen in older normal subjects, and the much larger values in patients with lung disease. We conclude that this noninvasive measurement of the efficiency of pulmonary exchange is identical in many respects to that based on the ideal alveolar Po2, but that it is easier to obtain.


Assuntos
Artérias/metabolismo , Pulmão/metabolismo , Oxigênio/metabolismo , Troca Gasosa Pulmonar/fisiologia , Dióxido de Carbono/metabolismo , Hemoglobinas/metabolismo , Humanos , Pulmão/fisiopatologia , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Oximetria/métodos , Respiração
12.
Cardiovasc Pathol ; 49: 107241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32554057

RESUMO

In order to accelerate development of atherosclerosis(AS) in miniature swine models, varieties of strategies and methods have been explored. In addition to traditional methods such as high cholesterol feeding and balloon injury, new methods such as familial hypercholesterolemia induced by gene editing and intramural injection have been applied in recent years. Although it has been claimed that these methods have successfully aggravated lesion areas and stenosis, lesion features induced by different strategies have shown heterogeneity in morphology. In addition, time consumption, high cost, and unavailability are problems that restrict application of these AS models. Here, we summarize strategies and methods to accelerate AS models and further analyze their values, advantages, and shortcomings.


Assuntos
Artérias/patologia , Aterosclerose/etiologia , Placa Aterosclerótica , Angioplastia com Balão , Animais , Animais Geneticamente Modificados , Artérias/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Edição de Genes , Predisposição Genética para Doença , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Suínos , Porco Miniatura/genética , Fatores de Tempo
13.
Arterioscler Thromb Vasc Biol ; 40(7): e193-e202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32404005

RESUMO

Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response-a complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.


Assuntos
Envelhecimento/patologia , Artérias/patologia , Aterosclerose/patologia , Dano ao DNA , Estresse Oxidativo , Placa Aterosclerótica , Calcificação Vascular/patologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Apatitas/metabolismo , Artérias/efeitos dos fármacos , Artérias/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Senescência Celular , Dano ao DNA/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Osteogênese , Estresse Oxidativo/efeitos dos fármacos , Poli Adenosina Difosfato Ribose/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
14.
Arterioscler Thromb Vasc Biol ; 40(7): 1627-1634, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434408

RESUMO

Peripheral artery disease is a common disorder and a major cause of morbidity and mortality worldwide. Therapy is directed at reducing the risk of major adverse cardiovascular events and at ameliorating symptoms. Medical therapy is effective at reducing the incidence of myocardial infarction and stroke to which these patients are prone but is inadequate in relieving limb-related symptoms, such as intermittent claudication, rest pain, and ischemic ulceration. Limb-related morbidity is best addressed with surgical and endovascular interventions that restore perfusion. Current medical therapies have only modest effects on limb blood flow. Accordingly, there is an opportunity to develop medical approaches to restore limb perfusion. Vascular regeneration to enhance limb blood flow includes methods to enhance angiogenesis, arteriogenesis, and vasculogenesis using angiogenic cytokines and cell therapies. We review the molecular mechanisms of these processes; briefly discuss what we have learned from the clinical trials of angiogenic and cell therapies; and conclude with an overview of a potential new approach based upon transdifferentiation to enhance vascular regeneration in peripheral artery disease.


Assuntos
Indutores da Angiogênese/uso terapêutico , Artérias/efeitos dos fármacos , Citocinas/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Doença Arterial Periférica/terapia , Regeneração/efeitos dos fármacos , Transplante de Células-Tronco , Animais , Artérias/metabolismo , Artérias/patologia , Artérias/fisiopatologia , Humanos , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/patologia , Doença Arterial Periférica/fisiopatologia , Recuperação de Função Fisiológica , Fluxo Sanguíneo Regional , Resultado do Tratamento
15.
Am J Physiol Heart Circ Physiol ; 319(1): H144-H158, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32442021

RESUMO

Pyridine nucleotides, such as NADPH and NADH, are emerging as critical players in the regulation of heart and vascular function. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is the primary source and regulator of cellular NADPH. In the current study, we have identified two isoforms of G6PD (slow and fast migrating) and functionally characterized the slow migrating isoform of G6PD (G6PD545) in bovine and human arteries. We found that G6PD545 is eluted in the caveolae fraction of vascular smooth muscle (VSM) and has a higher maximum rate of reaction (Vmax: 1.65-fold) than its fast migrating isoform (G6PD515). Interestingly, caveolae G6PD forms a complex with the pore-forming α1C-subunit of the L-type Ca2+ channel, Cav1.2, as demonstrated by a proximity ligation assay in fixed VSMCs. Additionally, Förster resonance energy transfer (FRET) analysis of HEK293-17T cells cotransfected with red fluorescent protein (RFP)-tagged G6PD545 (C-G6PD545) and green fluorescent protein (GFP)-tagged Cav1.2-(Cav1.2-GFP) demonstrated strong FRET signals as compared with cells cotransfected with Cav1.2-GFP and C-G6PD515. Furthermore, L-type Ca2+ channel conductance was larger and the voltage-independent component of availability (c1) was augmented in C-G6PD545 and Cav1.2-GFP cotransfectants compared with those expressing Cav1.2-GFP alone. Surprisingly, epiandrosterone, a G6PD inhibitor, disrupted the G6PD-Cav1.2 complex, also decreasing the amplitude of L-type Ca2+ currents and window currents, thereby reducing the availability of the c1 component. Moreover, overexpression of adeno-G6PD545-GFP augmented the KCl-induced contraction in coronary arteries compared with control. To determine whether overexpression of G6PD had any clinical implication, we investigated its activity in arteries from patients and rats with metabolic syndrome and found that G6PD activity was high in this disease condition. Interestingly, epiandrosterone treatment reduced elevated mean arterial blood pressure and peripheral vascular resistance in metabolic syndrome rats, suggesting that the increased activity of G6PD augmented vascular contraction and blood pressure in the metabolic syndrome. These data suggest that the novel G6PD-Cav1.2 interaction, in the caveolae fraction, reduces intrinsic voltage-dependent inactivation of the channel and contributes to regulate VSM L-type Ca2+ channel function and Ca2+ signaling, thereby playing a significant role in modulating vascular function in physiological/pathophysiological conditions.NEW & NOTEWORTHY In this study we have identified a novel isozyme of glucose-6-phosphate dehydrogenase (G6PD), a metabolic enzyme, that interacts with and contributes to regulate smooth muscle cell l-type Ca2+ ion channel function, which plays a crucial role in vascular function in physiology and pathophysiology. Furthermore, we demonstrate that expression and activity of this novel G6PD isoform are increased in arteries of individuals with metabolic syndrome and in inhibition of G6PD activity in rats of metabolic syndrome reduced blood pressure.


Assuntos
Artérias/metabolismo , Canais de Cálcio Tipo L/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Potenciais de Ação , Androsterona/farmacologia , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Pressão Sanguínea , Bovinos , Cavéolas/metabolismo , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Células HEK293 , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Ligação Proteica , Transporte Proteico , Ratos , Ratos Sprague-Dawley , Vasoconstrição
16.
Sci Rep ; 10(1): 8545, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444654

RESUMO

Vascular calcification occurs in various diseases including atherosclerosis, chronic kidney disease and type 2 diabetes but the mechanism underlying mineral deposition remains incompletely understood. Here we examined lower limb arteries of type 2 diabetes subjects for the presence of ectopic calcification and mineral particles using histology, electron microscopy and spectroscopy analyses. While arteries of healthy controls showed no calcification following von Kossa staining, arteries from 83% of diabetic individuals examined (19/23) revealed microscopic mineral deposits, mainly within the tunica media. Mineralo-organic particles containing calcium phosphate and proteins such as albumin, fetuin-A and apolipoprotein-A1 were detected in calcified arteries. Ectopic calcification and mineralo-organic particles were observed in a majority of diabetic patients and predominantly in arteries showing hyperplasia. While a low number of subjects was examined and information about disease severity and patient characteristics is lacking, these calcifications and mineralo-organic particles may represent signs of tissue dysfunction.


Assuntos
Artérias/patologia , Arteriosclerose/patologia , Calcinose/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Minerais/metabolismo , Compostos Orgânicos/metabolismo , Artérias/metabolismo , Arteriosclerose/metabolismo , Calcinose/metabolismo , Fosfatos de Cálcio/metabolismo , Estudos de Casos e Controles , Humanos , Minerais/química , Compostos Orgânicos/química
18.
Arterioscler Thromb Vasc Biol ; 40(5): 1078-1093, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32237904

RESUMO

This review focuses on the association between vascular calcification and arterial stiffness, highlighting the important genetic factors, systemic and local microenvironmental signals, and underlying signaling pathways and molecular regulators of vascular calcification. Elevated oxidative stress appears to be a common procalcification factor that induces osteogenic differentiation and calcification of vascular cells in a variety of disease conditions such as atherosclerosis, diabetes mellitus, and chronic kidney disease. Thus, the role of oxidative stress and oxidative stress-regulated signals in vascular smooth muscle cells and their contributions to vascular calcification are highlighted. In relation to diabetes mellitus, the regulation of both hyperglycemia and increased protein glycosylation, by AGEs (advanced glycation end products) and O-linked ß-N-acetylglucosamine modification, and its role in enhancing intracellular pathophysiological signaling that promotes osteogenic differentiation and calcification of vascular smooth muscle cells are discussed. In the context of chronic kidney disease, this review details the role of calcium and phosphate homeostasis, parathyroid hormone, and specific calcification inhibitors in regulating vascular calcification. In addition, the impact of the systemic and microenvironmental factors on respective intrinsic signaling pathways that promote osteogenic differentiation and calcification of vascular smooth muscle cells and osteoblasts are compared and contrasted, aiming to dissect the commonalities and distinctions that underlie the paradoxical vascular-bone mineralization disorders in aging and diseases.


Assuntos
Artérias/fisiopatologia , Osteogênese , Calcificação Vascular/fisiopatologia , Remodelação Vascular , Rigidez Vascular , Fatores Etários , Animais , Artérias/metabolismo , Artérias/patologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Diabetes Mellitus/fisiopatologia , Predisposição Genética para Doença , Humanos , Nefropatias/epidemiologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Estresse Oxidativo , Fatores de Risco , Transdução de Sinais , Calcificação Vascular/epidemiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
19.
J Vasc Res ; 57(3): 152-163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32248195

RESUMO

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.


Assuntos
Artérias/efeitos dos fármacos , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Amidas , Animais , Artérias/inervação , Artérias/metabolismo , Estado de Descerebração , Estimulação Elétrica , Masculino , Norepinefrina/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Sistema Nervoso Simpático/fisiologia , Simpatomiméticos/farmacologia , Canais de Cátion TRPV/metabolismo
20.
J Vis Exp ; (157)2020 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-32281975

RESUMO

Neutrophil extracellular traps (NETs), composed of cell-free DNA (cfDNA) and proteins like histones and neutrophil elastase (NE), are released by neutrophils in response to systemic inflammation or pathogens. Although NETs have previously been shown to augment clot formation and inhibit fibrinolysis in humans and dogs, the role of NETs in cats with cardiogenic arterial thromboembolism (CATE), a life-threatening complication secondary to hypertrophic cardiomyopathy, is unknown. A standardized method to identify and quantify NETs in cardiogenic arterial thrombi in cats will advance our understanding of their pathological role in CATE. Here, we describe a technique to identify NETs in formaldehyde-fixed and paraffin-embedded thrombi within the aortic bifurcation, extracted during necropsy. Following deparaffinization with xylene, aortic sections underwent indirect heat-induced antigen retrieval. Sections were then blocked, permeabilized, and ex vivo NETs were identified by colocalization of cell-free DNA (cfDNA), citrullinated histone H3 (citH3), and neutrophil elastase (NE) using immunofluorescence microscopy. To optimize the immunodetection of NETs in thrombi, autofluorescence of tissue elements was limited by using an autofluorescence quenching process prior to microscopy. This technique could be a useful tool to study NETs and thrombosis in other species and offers new insights into the pathophysiology of this complex condition.


Assuntos
Artérias/metabolismo , Armadilhas Extracelulares/metabolismo , Microscopia de Fluorescência/métodos , Neutrófilos/metabolismo , Inclusão em Parafina/métodos , Animais , Gatos
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