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1.
Oxid Med Cell Longev ; 2022: 7192507, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338347

RESUMO

Vascular calcification (VC) is regarded as a common feature of vascular aging. Klotho deficiency reportedly contributes to VC, which can be ameliorated by restoration of Klotho expression. However, the specific mechanisms involved remain unclear. Here, we investigated the role of autophagy in the process of Klotho-inhibiting VC. The clinical study results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells (MOVAS) under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification. This study is beneficial to exploring the underlying mechanisms of Klotho regulating VC, which has important guiding significance for future clinical studies in the treatment of VC.


Assuntos
Calcificação Vascular , Camundongos , Animais , Calcificação Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Autofagia , Aorta/metabolismo , Glucuronidase/genética , Glucuronidase/metabolismo
2.
Int J Mol Sci ; 23(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36362244

RESUMO

Elastic fibers, made of elastin (90%) and fibrillin-rich microfibrils (10%), are the key extracellular components, which endow the arteries with elasticity. The alteration of elastic fibers leads to cardiovascular dysfunctions, as observed in elastin haploinsufficiency in mice (Eln+/-) or humans (supravalvular aortic stenosis or Williams-Beuren syndrome). In Eln+/+ and Eln+/- mice, we evaluated (arteriography, histology, qPCR, Western blots and cell cultures) the beneficial impact of treatment with a synthetic elastic protein (SEP), mimicking several domains of tropoelastin, the precursor of elastin, including hydrophobic elasticity-related domains and binding sites for elastin receptors. In the aorta or cultured aortic smooth muscle cells from these animals, SEP treatment induced a synthesis of elastin and fibrillin-1, a thickening of the aortic elastic lamellae, a decrease in wall stiffness and/or a strong trend toward a reduction in the elastic lamella disruptions in Eln+/- mice. SEP also modified collagen conformation and transcript expressions, enhanced the aorta constrictive response to phenylephrine in several animal groups, and, in female Eln+/- mice, it restored the normal vasodilatory response to acetylcholine. SEP should now be considered as a biomimetic molecule with an interesting potential for future treatments of elastin-deficient patients with altered arterial structure/function.


Assuntos
Doenças Vasculares , Síndrome de Williams , Humanos , Camundongos , Masculino , Feminino , Animais , Elastina/metabolismo , Tecido Elástico/metabolismo , Haploinsuficiência , Aorta/metabolismo , Doenças Vasculares/patologia
3.
PLoS One ; 17(11): e0265854, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36395179

RESUMO

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder which induces endothelial dysfunction and platelet activation. Eicosanoids produced from arachidonic acid regulate cellular and vascular functions. Sigma-1 receptors (S1R) are expressed in platelets and endothelial cells and S1R expression is protective in diabetes. OBJECTIVES: Our aim was to examine the influence of sub-chronic, in vivo administered S1R ligands PRE-084, (S)-L1 (a new compound) and NE-100 on the ex vivo arachidonic acid metabolism of platelets and aorta in streptozotocin-induced diabetic rats. METHODS: The serum level of the S1R ligands was detected by LC-MS/MS before the ex vivo analysis. Sigma-1 receptor and cyclooxygenase gene expression in platelets were determined by RT-qPCR. The eicosanoid synthesis was examined with a radiolabelled arachidonic acid substrate and ELISA. RESULTS: One month after the onset of STZ-induced diabetes, in vehicle-treated, diabetic rat platelet TxB2 and aortic 6-k-PGF1α production dropped. Sub-chronic in vivo treatment of STZ-induced diabetes in rats for one week with PRE-084 enhanced vasoconstrictor and platelet aggregator and reduced vasodilator and anti-aggregator cyclooxygenase product formation. (S)-L1 reduced the synthesis of vasodilator and anti-aggregator cyclooxygenase metabolites and promoted the recovery of physiological platelet function in diabetic rats. The S1R antagonist NE-100 produced no significant changes in platelet arachidonic acid metabolism. (S)-L1 decreased the synthesis of vasoconstrictor and platelet aggregator cyclooxygenase metabolites, whereas NE-100 increased the quantity of aortic vasodilator and anti-aggregator cyclooxygenase products and promoted the recovery of diabetic endothelial dysfunction in the aorta. The novel S1R ligand, (S)-L1 had similar effects on eicosanoid synthesis in platelets as the agonist PRE-084 and in aortas as the antagonist NE-100. CONCLUSIONS: S1R ligands regulate cellular functions and local blood circulation by influencing arachidonic acid metabolism. In diabetes mellitus, the cell-specific effects of S1R ligands have a compensatory role and aid in restoring physiological balance between the platelet and vessel.


Assuntos
Diabetes Mellitus Experimental , Animais , Ratos , Estreptozocina , Ácido Araquidônico/farmacologia , Diabetes Mellitus Experimental/metabolismo , Ligantes , Células Endoteliais/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ácidos Araquidônicos/metabolismo , Aorta/metabolismo , Eicosanoides , Ciclo-Oxigenase 2 , Vasodilatadores , Vasoconstritores
4.
Biomolecules ; 12(11)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36358914

RESUMO

Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase (LOX) are vascular enzymes associated with the development of atherosclerosis. In the vascular smooth muscle cells, increased SSAO activity elevates reactive oxygen species (ROS) and induces VSMCs death; increased LOX induces chemotaxis through hydrogen peroxide dependent mechanisms; and decreased LOX contributes to endothelial dysfunction. This study investigates the relationship between SSAO and LOX in VSMCs by studying their activity, protein, and mRNA levels during VSMCs passaging and after silencing the LOX gene, while using their respective substrates and inhibitors. At the basal level, LOX activity decreased with passage and its protein expression was maintained between passages. ßAPN abolished LOX activity (** p < 0.01 for 8 vs. 3 and * p < 0.05 for 5 vs. 8) and had no effect on LOX protein and mRNA levels. MDL72527 reduced LOX activity at passage 3 and 5 (##&nbsp;p < 0.01) and had no effect on LOX protein, and mRNA expression. At the basal level, SSAO activity also decreased with passage, and its protein expression was maintained between passages. MDL72527 abolished SSAO activity (****&nbsp;p < 0.0001 for 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 5 (** p < 0.01) and 8 (**** p < 0.0001), and Aoc3 mRNA levels at passage 8 (* p < 0.05). ßAPN inhibited SSAO activity (**** p < 0.0001 for 5 vs. 3 and 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 3 (* p < 0.05), and Aoc3 mRNA levels at passage 3 (* p < 0.05). Knockdown of the LOX gene (**** p < 0.0001 for Si6 vs. Sictrl and *** p < 0.001 for Si8 vs. Sictrl) and LOX protein (** p < 0.01 for Si6 and Si8 vs. Sictrl) in VSMCs at passage 3 resulted in a reduction in Aoc3 mRNA (####&nbsp;p < 0.0001 for Si6 vs. Sictrl and ###&nbsp;p < 0.001 for Si8 vs. Sictrl) and VAP-1 protein (#&nbsp;p < 0.05 for Si8 vs. Sictrl). These novel findings demonstrate a passage dependent decrease in LOX activity and increase in SSAO activity in rat aortic VSMCs and show an association between both enzymes in early passage rat aortic VSMCs, where LOX was identified as a regulator of SSAO activity, protein, and mRNA expression.


Assuntos
Amina Oxidase (contendo Cobre) , Ratos , Animais , Amina Oxidase (contendo Cobre)/genética , Amina Oxidase (contendo Cobre)/metabolismo , Músculo Liso Vascular/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Aorta/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
Biosens Bioelectron ; 218: 114747, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36198238

RESUMO

Thoracic aortic aneurysm (TAA), in which arteries enlarge asymptomatically over time until dissection or rupture occurs, is a serious health risk. The mainstay of TAA treatment remains surgical repair due to the lack of effective drugs. The complex etiology and pathogenesis of TAA, including hemodynamic alterations and genetic factors, lead to inaccuracies in preclinical models for drug screening. Previously, our group designed an aorta smooth muscle-on-a-chip to emulate human aorta physiology and pathophysiology and screened three promising therapeutic drugs targeting mitochondrial dynamics in TAA. On this foundation, we updated the one-channel chip to an eighteen-well chip platform with four polydimethylsiloxane layers. Benefiting from this high-throughput chip, we rapidly screened multiple drugs simultaneously using distinct cell lines in vitro. In addition, we observed the abnormal activation of hypoxia-inducible factor 1-alpha (HIF-1alpha) in aortas from TAA patients by Western blot and bioinformatics analyses. Intriguingly, this phenomenon was replicated only when smooth muscle cells (SMCs) were strained on the chip. We then screened seven specific HIF-1alpha inhibitors and selected the two most effective drugs (2-methoxyestradiol and digoxin) by quantitative PCR and colorimetric methods. The results demonstrated that these two drugs can improve respiratory chain function and rescue the SMC contractile phenotype, showing applicability for the clinical treatment of TAA. This high-throughput aorta smooth muscle-on-a-chip will become a potential preclinical model for TAA drug screening.


Assuntos
Aneurisma da Aorta Torácica , Técnicas Biossensoriais , Humanos , Aneurisma da Aorta Torácica/tratamento farmacológico , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , 2-Metoxiestradiol/metabolismo , Avaliação Pré-Clínica de Medicamentos , Dispositivos Lab-On-A-Chip , Aorta/metabolismo , Aorta/patologia , Digoxina , Dimetilpolisiloxanos , Fator 1 Induzível por Hipóxia/metabolismo , Músculo Liso/metabolismo , Músculo Liso/patologia
6.
Exp Cell Res ; 421(2): 113386, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36244410

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening disorder that occurs in the aorta. The inflammatory thickness of the aneurysm wall and perianeurysmal fibrosis are two main causes of AAA pathogenesis; however, the molecular mechanisms involved in these two processes are still unclear. We discovered that C-terminal binding protein 1 (CtBP1) and CtBP2 were overexpressed in the aortas of AAA-model mice created by treatment with CaCl2 and elastase. Molecular analyses revealed that the CtBP heterodimer couples with histone acetyltransferase p300 and transcription factor AP1 (activator protein 1) to transactivate a set of matrix metalloproteinases (MMPs, including MMP1a, 3, 7, 9, and 12) and proinflammatory cytokines, including interleukin-1 ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α). Knockdown of CtBPs or AP1 subunits or blockage of CtBPs with specific small molecule inhibitors significantly suppressed the in vitro expression of MMPs and proinflammatory cytokines. The administration of CtBP inhibitors in AAA-model mice also inhibited MMPs and proinflammatory cytokines, thereby improving the AAA outcome. Taken together, our results revealed a new regulatory mechanism involving MMPs and proinflammatory cytokines in the pathogenesis of AAA. This discovery suggests that targeting CtBPs may be a therapeutic strategy for AAA by attenuating the inflammatory response and matrix destruction.


Assuntos
Aneurisma da Aorta Abdominal , Camundongos , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Citocinas/genética , Metaloproteinases da Matriz/genética , Aorta/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Modelos Animais de Doenças
7.
Sci Rep ; 12(1): 17167, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229484

RESUMO

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular disease. While intermittent hypoxia (IH) and catecholamine release play an important role in this increased risk, the mechanisms are incompletely understood. We have recently reported that IH causes endothelial cell (EC) activation, an early phenomenon in the development of cardiovascular disease, via IH-induced catecholamine release. Here, we investigated the effects of IH and epinephrine on gene expression in human aortic ECs using RNA-sequencing. We found a significant overlap between IH and epinephrine-induced differentially expressed genes (DEGs) including enrichment in leukocyte migration, cytokine-cytokine receptor interaction, cell adhesion and angiogenesis. Epinephrine caused higher number of DEGs compared to IH. Interestingly, IH when combined with epinephrine had an inhibitory effect on epinephrine-induced gene expression. Combination of IH and epinephrine induced MT1G (Metallothionein 1G), which has been shown to be highly expressed in ECs from parts of aorta (i.e., aortic arch) where atherosclerosis is more likely to occur. In conclusion, epinephrine has a greater effect than IH on EC gene expression in terms of number of genes and their expression level. IH inhibited the epinephrine-induced transcriptional response. Further investigation of the interaction between IH and epinephrine is needed to better understand how OSA causes cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Apneia Obstrutiva do Sono , Aorta/metabolismo , Doenças Cardiovasculares/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Epinefrina/metabolismo , Epinefrina/farmacologia , Humanos , Hipóxia/metabolismo , Metalotioneína/metabolismo , RNA/metabolismo , Receptores de Citocinas/metabolismo
8.
ACS Infect Dis ; 8(11): 2271-2290, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36083791

RESUMO

Chagas disease is an emerging global health problem; however, it remains neglected. Increased aortic stiffness (IAS), a predictor of cardiovascular events, has recently been reported in asymptomatic chronic Chagas patients. After vascular injury, smooth muscle cells (SMCs) can undergo alterations associated with phenotypic switch and transdifferentiation, promoting vascular remodeling and IAS. By studying different mouse aortic segments, we tested the hypothesis that Trypanosoma cruzi infection promotes vascular remodeling. Interestingly, the thoracic aorta was the most affected by the infection. Decreased expression of SMC markers and increased expression of proliferative markers were observed in the arteries of acutely infected mice. In acutely and chronically infected mice, we observed cells coexpressing SMC and macrophage (Mo) markers in the media and adventitia layers of the aorta, indicating that T. cruzi might induce cellular processes associated with SMC transdifferentiation into Mo-like cells or vice versa. In the adventitia, the Mo cell functional polarization was associated with an M2-like CD206+arginase-1+ phenotype despite the T. cruzi presence in the tissue. Only Mo-like cells in inflammatory foci were CD206+iNOS+. In addition to the disorganization of elastic fibers, we found thickening of the aortic layers during the acute and chronic phases of the disease. Our findings indicate that T. cruzi infection induces a vascular remodeling with SMC dedifferentiation and increased cell populations coexpressing α-SMA and Mo markers that could be associated with IAS promotion. These data highlight the importance of studying large vessel homeostasis in Chagas disease.


Assuntos
Doença de Chagas , Remodelação Vascular , Camundongos , Animais , Actinas/metabolismo , Macrófagos/metabolismo , Aorta/metabolismo , Biomarcadores , Músculo Liso/metabolismo
9.
Biometals ; 35(6): 1325-1339, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36178540

RESUMO

Vascular calcification (VC) has been associated with a risk of cardiovascular diseases. Iron may play a critical role in progressive VC. Therefore, we investigated the effects of iron overload on the aorta of rats. A rat model of iron overload was established by intraperitoneal injection of Iron-Dextran. The levels of iron, calcium, and ALP activity were detected. Von Kossa staining and Perl's staining were conducted. The expression of iron metabolism-related and calcification related factors were examined in the aortic tissue of rats. The results showed serum and aortic tissue iron were increased induced by iron overload and excessive iron induced hepatic and renal damage. In iron overload rats, the expression of divalent metal transporter 1 (DMT1) and hepcidin were higher, but ferroportin1 (FPN1) was lower. Von Kossa staining demonstrated calcium deposition in the aorta of iron overload rats. The calcium content and ALP activity in serum and aortic tissue were increased and iron level in aortic tissue highly correlated with calcium content and ALP activity. The expressions of the osteogenic markers were increased while a decrease of Alpha-smooth muscle actin (α-SMA) in the aortic tissue of iron overload rats. IL-24 was increased during the calcification process induced by iron. Overall, we demonstrated excessive iron accumulation in the aortic tissue and induced organs damage. The iron metabolism-related factors were significantly changed during iron overload. Moreover, we found that iron overload leads to calcium deposition in aorta, playing a key role in the pathological process of VC by mediating osteoblast differentiation factors.


Assuntos
Sobrecarga de Ferro , Calcificação Vascular , Ratos , Animais , Cálcio/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Sobrecarga de Ferro/metabolismo , Aorta/metabolismo , Aorta/patologia , Rim/metabolismo , Ferro/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 323(5): H917-H933, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36083796

RESUMO

We have shown that excessive endothelial cell stretch causes release of growth arrest-specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model of aortic remodeling in mice following a 2-wk infusion of angiotensin II (ANG II). These mice had chronically increased pulse wave velocity, and their aortas demonstrated increased mural collagen. Mechanical testing revealed a marked loss of Windkessel function that persisted for 6 mo following ANG II infusion. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria, and tubular damage as estimated by periodic acid Schiff staining. Treatment with the Axl inhibitor R428 beginning 2 mo after ANG II infusion had a minimal effect on aortic remodeling 2 mo later but reduced the infiltration of T cells, γ/δ T cells, and macrophages into the aorta and kidney and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl+/Siglec6+ dendritic cells and phospho-Axl+ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling, which is associated with persistent low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.NEW & NOTEWORTHY In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8+ and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.


Assuntos
Hipertensão , Nefropatias , Animais , Humanos , Camundongos , Albuminúria/prevenção & controle , Angiotensina II/farmacologia , Aorta/metabolismo , Colágeno , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Ácido Periódico , Proteínas Proto-Oncogênicas/metabolismo , Análise de Onda de Pulso , Receptores Proteína Tirosina Quinases/metabolismo
11.
Int J Mol Sci ; 23(18)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36142762

RESUMO

The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-ß-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.


Assuntos
Doença da Válvula Aórtica Bicúspide , Doenças das Valvas Cardíacas , Aorta/metabolismo , Valva Aórtica/metabolismo , Biomarcadores/metabolismo , Endotélio/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Humanos , Fatores de Transcrição/metabolismo , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo , Fator de Crescimento Transformador beta/metabolismo
12.
Biomed Pharmacother ; 154: 113640, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36081286

RESUMO

Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.


Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipidemias , Complexo Vitamínico B , Animais , Aorta/metabolismo , Aterosclerose/metabolismo , Colesterol , Dieta Aterogênica , Homocisteína/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hiperlipidemias/metabolismo , Coelhos
13.
Int J Mol Sci ; 23(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36012557

RESUMO

Recent evidence from our laboratory suggests that impeding ER stress-GSK3α/ß signaling attenuates the progression and development of atherosclerosis in mouse model systems. The objective of this study was to determine if the tissue-specific genetic ablation of GSK3α/ß could promote the regression of established atherosclerotic plaques. Five-week-old low-density lipoprotein receptor knockout (Ldlr-/-) mice were fed a high-fat diet for 16 weeks to promote atherosclerotic lesion formation. Mice were then injected with tamoxifen to induce macrophage-specific GSK3α/ß deletion, and switched to standard diet for 12 weeks. All mice were sacrificed at 33 weeks of age and atherosclerosis was quantified and characterized. Female mice with induced macrophage-specific GSK3α deficiency, but not GSK3ß deficiency, had reduced plaque volume (~25%) and necrosis (~40%) in the aortic sinus, compared to baseline mice. Atherosclerosis was also significantly reduced (~60%) in the descending aorta. Macrophage-specific GSK3α-deficient mice showed indications of increased plaque stability and reduced inflammation in plaques, as well as increased CCR7 and ABCA1 expression in lesional macrophages, consistent with regressive plaques. These results suggest that GSK3α ablation promotes atherosclerotic plaque regression and identify GSK3α as a potential target for the development of new therapies to treat existing atherosclerotic lesions in patients with cardiovascular disease.


Assuntos
Aterosclerose , Quinase 3 da Glicogênio Sintase , Placa Aterosclerótica , Animais , Aorta/metabolismo , Aterosclerose/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Deleção de Genes , Quinase 3 da Glicogênio Sintase/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/patologia , Proteínas Serina-Treonina Quinases , Receptores de LDL/metabolismo
14.
J Smooth Muscle Res ; 58(0): 63-77, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35944980

RESUMO

PURPOSE: This study aimed to verify whether Adjuvant-Induced Arthritis (AIA) and/or Orchiectomy (ORX) modify the expression of the Nox1, Nox2 and Nox4 isoforms, the endothelial function or the structure of rat aortas. METHODS: Sixty-three Wistar rats were distributed into four groups: 1) Control; 2) ORX; 3) AIA; 4) Orchiectomy plus to Arthritis-induction (ORX/AIA). Thus, 21 days after the onset of AIA (by intradermal injection of Mycobacterium tuberculosis), the presence of Nox1, Nox2 and Nox4, the acetylcholine (ACh)-induced relaxation and the media layer thickness were assessed in the aorta taken from these animals. RESULTS: The Nox1, Nox2 and Nox4 were immunostained in intima, media and adventitia layers of aortas taken from all studied groups and AIA apparently increased this immunostaining. These modifications of Nox1, Nox2 or Nox4 expression, however, were not confirmed by Western blotting. In addition, neither AIA nor ORX changed the endothelial function, but ORX increased the media layer thickness in the studied aortas. CONCLUSION: The present study showed weak clues of increased expression of Nox1, Nox2 and Nox4 as a result of AIA, as well as of Nox1 reduction caused by ORX. In addition, the endothelial function was not modified in the aortas of these animals by both AIA and/or ORX. On the other hand, ORX increased significantly the aorta media layer thickness in the studied animals, which was apparently mitigated by AIA.


Assuntos
Artrite Experimental , Endotélio Vascular , Animais , Aorta/metabolismo , Artrite Experimental/metabolismo , Endotélio Vascular/metabolismo , Masculino , Orquiectomia , Ratos , Ratos Wistar
15.
Dev Biol ; 490: 134-143, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35917935

RESUMO

The vertebrate embryonic midline vasculature forms in close proximity to the developing skeletal muscle, which originates in the somites. Angioblasts migrate from bilateral positions along the ventral edge of the somites until they meet at the midline, where they sort and differentiate into the dorsal aorta and the cardinal vein. This migration occurs at the same time that myoblasts in the somites are beginning to differentiate into skeletal muscle, a process which requires the activity of the basic helix loop helix (bHLH) transcription factors Myod and Myf5. Here we examined vasculature formation in myod and myf5 mutant zebrafish. In the absence of skeletal myogenesis, angioblasts migrate normally to the midline but form only the cardinal vein and not the dorsal aorta. The phenotype is due to the failure to activate vascular endothelial growth factor ligand vegfaa expression in the somites, which in turn is required in the adjacent angioblasts for dorsal aorta specification. Myod and Myf5 cooperate with Hedgehog signaling to activate and later maintain vegfaa expression in the medial somites, which is required for angiogenic sprouting from the dorsal aorta. Our work reveals that the early embryonic skeletal musculature in teleosts evolved to organize the midline vasculature during development.


Assuntos
Proteína MyoD , Fatores de Regulação Miogênica , Animais , Aorta/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas Musculares/genética , Músculo Esquelético , Proteína MyoD/genética , Proteína MyoD/metabolismo , Fator Regulador Miogênico 5/genética , Fator Regulador Miogênico 5/metabolismo , Fatores de Regulação Miogênica/genética , Fatores de Regulação Miogênica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
16.
Biomolecules ; 12(8)2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-36009019

RESUMO

Aging impairs the expression of HSP70, an emergent player in vascular biology. However, it is unknown if age-related alterations in HSP70 are linked to a decline in arterial function. In this study, we test the hypothesis that the contributions of HSP70 to vascular contraction are diminished in middle-aged animals. We determined the basal levels of HSP70 in the aorta of young and middle-aged Sprague Dawley male rats using Western blotting. Functional studies were performed in a wire myograph system. Force development in response to phenylephrine was assessed in the presence or absence of extracellular calcium (Ca2+), and in aortic rings treated or non-treated with an HSP70 inhibitor. Fluorescent probes were used to evaluate vascular oxidative stress and nitric oxide levels. We report that middle-aged rats have significantly lower levels of HSP70. Blockade of HSP70 attenuated vascular phasic and tonic contraction in isolated aortas. It appears that a functional HSP70 is required for proper Ca2+ handling as inhibition of this protein led to reduced force-displacement in response to Ca2+ dynamics. Furthermore, middle-aged aortic rings exposed to the HSP70 inhibitor display higher reactive oxygen species levels without changes in nitric oxide. In summary, we show that middle-aged animals have lower levels of HSP70 in aortas, which associates with an age-related decline in vascular responses to α-1 adrenergic stimulation.


Assuntos
Aorta , Óxido Nítrico , Animais , Aorta/metabolismo , Proteínas de Choque Térmico HSP70 , Masculino , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley
17.
Chemosphere ; 307(Pt 2): 135807, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35931261

RESUMO

Throughout human life, an extensive and varied range of emerging environmental contaminants, called endocrine disruptors (EDCs), cause adverse health effects, including in the cardiovascular (CV) system. Cardiovascular diseases (CVD) are worryingly one of the leading causes of all mortality and mobility worldwide. The UV-B filter octylmethoxycinnamate (also designated octinoxate, or ethylhexyl methoxycinnamate (CAS number: 5466-77-3)) is an EDC widely present in all personal care products. However, to date, there are no studies evaluating the OMC-induced effects on vasculature using animal models to improve human cardiovascular health. This work analysed the effects of OMC on rat aorta vasculature and explored the modes of action implicated in these effects. Our results indicated that OMC relaxes the rat aorta by endothelium-dependent mechanisms through the signaling pathways of cyclic nucleotides and by endothelium-independent mechanisms involving inhibition of L-Type voltage-operated Ca2+ channels (L-Type VOCC). Overall, OMC toxicity on rat aorta may produce hypotension via vasodilation due to excessive NO release and blockade of L-Type VOCC. Moreover, the OMC-induced endothelial dysfunction may also occur by promoting the endothelial release of endothelin-1. Therefore, our findings demonstrate that exposure to OMC alters the reactivity of the rat aorta and highlight that long-term OMC exposure may increase the risk of human CV diseases.


Assuntos
Disruptores Endócrinos , Animais , Aorta/metabolismo , Cinamatos , Disruptores Endócrinos/metabolismo , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Endotélio , Endotélio Vascular , Humanos , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/farmacologia , Ratos
18.
Int J Mol Sci ; 23(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35955709

RESUMO

High doses of ionizing radiation can cause cardiovascular diseases (CVDs); however, the effects of <100 mGy radiation on CVD remain underreported. Endothelial cells (ECs) play major roles in cardiovascular health and disease, and their function is reduced by stimuli such as chronic disease, metabolic disorders, and smoking. However, whether exposure to low-dose radiation results in the disruption of similar molecular mechanisms in ECs under diabetic and non-diabetic states remains largely unknown; we aimed to address this gap in knowledge through the molecular and functional characterization of primary human aortic endothelial cells (HAECs) derived from patients with type 2 diabetes (T2D-HAECs) and normal HAECs in response to low-dose radiation. To address these limitations, we performed RNA sequencing on HAECs and T2D-HAECs following exposure to 100 mGy of ionizing radiation and examined the transcriptome changes associated with the low-dose radiation. Compared with that in the non-irradiation group, low-dose irradiation induced 243 differentially expressed genes (DEGs) (133 down-regulated and 110 up-regulated) in HAECs and 378 DEGs (195 down-regulated and 183 up-regulated) in T2D-HAECs. We also discovered a significant association between the DEGs and the interferon (IFN)-I signaling pathway, which is associated with CVD by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein network analysis, and module analysis. Our findings demonstrate the potential impact of low-dose radiation on EC functions that are related to the risk of CVD.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Aorta/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica , Humanos , Transcriptoma
19.
Int J Immunopathol Pharmacol ; 36: 3946320221117933, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35932160

RESUMO

OBJECTIVES: T helper 17 (Th17) cells are involved in the inflammatory response of atherosclerosis. However, their heterogeneity in the atherosclerotic aorta remains elusive. This study was designed to identify aortic Th17 subsets. METHODS: The surface markers and transcription factors of aortic interleukin-17A (IL-17A)-expressing T cells were determined by flow cytometry in an ApoE-deficient mouse atherosclerotic model. Viable aortic IL-17A-expressing T cell subsets were isolated by flow cytometry on the basis of surface markers, followed by characterizing their transcription factors by either flow cytometry or real-time RT-PCR. The effect of aortic IL-17A-expressing T cell subsets on aortic endothelial cells was determined in vitro. RESULTS: C-X-C Motif Chemokine Receptor 3 (CXCR3), interleukin-17 receptor E (IL-17RE), CD200, and C-C Motif Chemokine Receptor 4 (CCR4) marked three subsets of aortic IL-17A-expressing T cells: CXCR3+IL-17RElowCD200+CCR4- T cells expressing T-box protein expressed in T cells (T-bet) and interferon-gamma (IFN-γ), CXCR3+IL-17RElowCD200+CCR4+ T cells expressing T-bet but fewer IFN-γ, and CXCR3-IL-17REhighCD200+CCR4+ T cells expressing very low T-bet and no IFN-γ. Based on these markers, viable aortic Th17 cells, Th17.1 cells, and transitional Th17.1 cells were identified. Both Th17.1 cells and transitional Th17.1 cells were more proliferative than Th17 cells. Compared with Th17 cells, Th17.1 cells plus transitional Th17.1 cells induced higher expression of C-X-C motif chemokine ligand 1 (CXCL1), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine 5 (CXCL5), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in aortic endothelial cells. CONCLUSION: IL-17A-expressing CD4+ T cells were heterogeneous in atherosclerotic aortas.


Assuntos
Aterosclerose , Interleucina-17 , Animais , Aorta/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Interferon gama/metabolismo , Interleucina-17/metabolismo , Ligantes , Camundongos , Receptores de Quimiocinas/metabolismo , Células Th17/metabolismo , Fatores de Transcrição/metabolismo
20.
Eur J Pharm Sci ; 178: 106284, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36038100

RESUMO

Abdominal aortic aneurysm (AAA) is a prevalent condition which causes progressive growth and rupture of aortic wall with a high death rate. Several studies have found that treatment with statins may decrease the progress of AAA and the risk of rupture by suppressing the inflammatory mediators, decreasing oxidative stress, and inhibiting mechanisms involved in extracellular matrix (ECM) degradation. Moreover, some studies have reported that prehospital therapy with statins can decrease mortality after surgery. The novelty of this paper is that different studies including those performed in humans and animals were reviewed and the potential mechanisms by which statins can have an effect on AAA were summarized. Overall, the evidence suggested an association between treatment with statins and improvement of AAA.


Assuntos
Aneurisma da Aorta Abdominal , Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Aorta/metabolismo , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Mediadores da Inflamação/metabolismo , Estresse Oxidativo
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