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1.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638650

RESUMO

Reactive oxygen species (ROS)-induced vascular endothelial cell apoptosis is strongly associated with atherosclerosis progression. Herein, we aimed to examine whether Kansuinine A (KA), extracted from Euphorbia kansui L., prevents atherosclerosis development in a mouse model and inhibits cell apoptosis through oxidative stress reduction. Atherosclerosis development was analyzed in apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD) using Oil Red O staining and H&E staining. Human aortic endothelial cells (HAECs) were treated with KA, followed by hydrogen peroxide (H2O2), to investigate the KA-mediated inhibition of ROS-induced oxidative stress and cell apoptosis. Oil Red O staining and H&E staining showed that atherosclerotic lesion size was significantly smaller in the aortic arch of ApoE-/- mice in the HFD+KA group than that in the aortic arch of those in the HFD group. Further, KA (0.1-1.0 µM) blocked the H2O2-induced death of HAECs and ROS generation. The H2O2-mediated upregulation of phosphorylated IKKß, phosphorylated IκBα, and phosphorylated NF-κB was suppressed by KA. KA also reduced the Bax/Bcl-2 ratio and cleaved caspase-3 expression, preventing H2O2-induced vascular endothelial cell apoptosis. Our results indicate that KA may protect against ROS-induced endothelial cell apoptosis and has considerable clinical potential in the prevention of atherosclerosis and cardiovascular diseases.


Assuntos
Aorta/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Diterpenos/farmacologia , Células Endoteliais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Aorta/metabolismo , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Quinase I-kappa B/metabolismo , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos
2.
Arterioscler Thromb Vasc Biol ; 41(11): 2671-2680, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34615376

RESUMO

The aorta is highly heterogeneous, containing many different types of cells that perform sophisticated functions to maintain aortic homeostasis. Recently, single-cell RNA sequencing studies have provided substantial new insight into the heterogeneity of vascular cell types, the comprehensive molecular features of each cell type, and the phenotypic interrelationship between these cell populations. This new information has significantly improved our understanding of aortic biology and aneurysms at the molecular and cellular level. Here, we summarize these findings, with a focus on what single-cell RNA sequencing analysis has revealed about cellular heterogeneity, cellular transitions, communications among cell populations, and critical transcription factors in the vascular wall. We also review the information learned from single-cell RNA sequencing that has contributed to our understanding of the pathogenesis of vascular disease, such as the identification of cell types in which aneurysm-related genes and genetic variants function. Finally, we discuss the challenges and future directions of single-cell RNA sequencing applications in studies of aortic biology and diseases.


Assuntos
Aorta/metabolismo , Aneurisma Aórtico/genética , Perfilação da Expressão Gênica , Análise de Célula Única , Transcriptoma , Animais , Aorta/patologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Dilatação Patológica , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA-Seq
3.
Nutrients ; 13(10)2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34684622

RESUMO

Cornelian cherry (Cornus mas L.) fruits possess potential cardiovascular, lipid-lowering and hypoglycemic bioactivities. The aim of this study is to evaluate the influence of resin-purified cornelian cherry extract rich in iridoids and anthocyanins on several transcription factors, intima/media ratio in aorta and serum parameters, which determine or are valuable indicators of the adverse changes observed in the course of atherosclerosis, cardiovascular disease, and metabolic syndrome. For this purpose, male New Zealand rabbits were fed a diet enriched in 1% cholesterol for 60 days. Additionally, one group received 10 mg/kg b.w. of cornelian cherry extract and the second group 50 mg/kg b.w. of cornelian cherry extract. PPAR-α and PPAR-γ expression in the aorta, LXR-α expression in the liver; cholesterol, triglycerides, adipokines, apolipoproteins, glucose and insulin levels in serum; the intima and media diameter in the thoracic and abdominal aorta were determined. Administration of cornelian cherry extract resulted in an enhancement in the expression of all tested transcription factors, a decrease in triglycerides, leptin and resistin, and an increase in adiponectin levels. In addition, a significant reduction in the I/M ratio was observed for both the thoracic and abdominal aorta. The results we have obtained confirm the potential contribution of cornelian cherry extract to mitigation of the risk of developing and the intensity of symptoms of obesity-related cardiovascular diseases and metabolic disorders such as atherosclerosis or metabolic syndrome.


Assuntos
Antocianinas/farmacologia , Doenças Cardiovasculares/prevenção & controle , Cornus/química , Iridoides/farmacologia , Síndrome Metabólica/prevenção & controle , Extratos Vegetais/farmacologia , Adipocinas/sangue , Animais , Aorta/metabolismo , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/metabolismo , Colesterol na Dieta/efeitos adversos , Humanos , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/metabolismo , PPAR gama/metabolismo , Coelhos , Triglicerídeos/sangue
4.
FASEB J ; 35(11): e21942, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34670018

RESUMO

Atherosclerosis is a chronic inflammatory disease. Pathophysiological similarities between chronic infections and atherosclerosis triggered interests between these conditions. The seroepidemiological study showed that Helicobacter pylori strains that express cytotoxin-associated gene A (CagA), an oncoprotein and a major virulence factor, was positively correlated with atherosclerosis and related clinical events. Nevertheless, the underlying mechanism is poorly understood. In this study, the seroprevalence of infection by H. pylori and by strains express CagA assessed by enzyme-linked immunosorbent assay (ELISA) showed that the prevalence of CagA strains rather than H. pylori in patients was positively correlated with atherogenesis. Correspondingly, we found that CagA augmented the growth of plaque of ApoE-/- mice in the early stage of atherosclerosis and promoted the expression of adhesion molecules and inflammatory cytokines in mouse aortic endothelial cells (MAECs). Mechanistically, both si-NLRP3 and si-IL-1ß mitigated the promoting effect of CagA on the inflammatory activation of HAECs. In vivo, the inhibition of NLRP3 by MCC950 significantly attenuated the promoting effect of CagA on plaque growth of ApoE-/- mice. We also propose NLRP3 as a potential therapeutic target for CagA-positive H. pylori infection-related atherosclerosis and emphasize the importance of inflammation in atherosclerosis pathology.


Assuntos
Antígenos de Bactérias/metabolismo , Aorta/patologia , Aterosclerose/sangue , Proteínas de Bactérias/metabolismo , Caspase 1/metabolismo , Células Endoteliais/metabolismo , Infecções por Helicobacter/sangue , Helicobacter pylori/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica/sangue , Idoso , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Aorta/metabolismo , Aterosclerose/microbiologia , Proteínas de Bactérias/imunologia , Modelos Animais de Doenças , Feminino , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Placa Aterosclerótica/microbiologia , Estudos Soroepidemiológicos , Células THP-1
5.
Arterioscler Thromb Vasc Biol ; 41(11): 2730-2739, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34587757

RESUMO

Objective: Species-specific pseudogenization of the CMAH gene during human evolution eliminated common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) biosynthesis from its precursor N-acetylneuraminic acid (Neu5Ac). With metabolic nonhuman Neu5Gc incorporation into endothelia from red meat, the major dietary source, anti-Neu5Gc antibodies appeared. Human-like Ldlr-/-Cmah-/- mice on a high-fat diet supplemented with a Neu5Gc-enriched mucin, to mimic human red meat consumption, suffered increased atherosclerosis if human-like anti-Neu5Gc antibodies were elicited. Approach and Results: We now ask whether interventional Neu5Ac feeding attenuates metabolically incorporated Neu5Gc-mediated inflammatory acceleration of atherogenesis in this Cmah-/-Ldlr-/- model system. Switching to a Neu5Gc-free high-fat diet or adding a 5-fold excess of Collocalia mucoid-derived Neu5Ac in high-fat diet protects against accelerated atherosclerosis. Switching completely from a Neu5Gc-rich to a Neu5Ac-rich diet further reduces severity. Remarkably, feeding Neu5Ac-enriched high-fat diet alone has a substantial intrinsic protective effect against atherosclerosis in Ldlr-/- mice even in the absence of dietary Neu5Gc but only in the human-like Cmah-null background. Conclusions: Interventional Neu5Ac feeding can mitigate or prevent the red meat/Neu5Gc-mediated increased risk for atherosclerosis, and has an intrinsic protective effect, even in the absence of Neu5Gc feeding. These findings suggest that similar interventions should be tried in humans and that Neu5Ac-enriched diets alone should also be investigated further.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Suplementos Nutricionais , Ácido N-Acetilneuramínico/administração & dosagem , Ácidos Neuramínicos/administração & dosagem , Placa Aterosclerótica , Ração Animal , Animais , Anticorpos/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Ácidos Neuramínicos/imunologia , Ácidos Neuramínicos/metabolismo , Pan troglodytes , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sialadenite/metabolismo , Sialadenite/patologia , Células THP-1
6.
J Biol Chem ; 297(4): 101152, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478715

RESUMO

Tissue factor (TF) is the principal initiator of blood coagulation and is necessary for thrombosis. We previously reported that lysophosphatidic acid (LPA), a potent bioactive lipid, highly induces TF expression at the transcriptional level in vascular smooth muscle cells. To date, however, the specific role of the LPA receptor is unknown, and the intracellular signaling pathways that lead to LPA induction of TF have been largely undetermined. In the current study, we found that LPA markedly induced protein kinase D (PKD) activation in mouse aortic smooth muscle cells (MASMCs). Small-interfering RNA-mediated knockdown of PKD2 blocked LPA-induced TF expression and activity, indicating that PKD2 is the key intracellular mediator of LPA signaling leading to the expression and cell surface activity of TF. Furthermore, our data reveal a novel finding that PKD2 mediates LPA-induced TF expression via the p38α and JNK2 MAPK signaling pathways, which are accompanied by the PKD-independent MEK1/2-ERK-JNK pathway. To identify the LPA receptor(s) responsible for LPA-induced TF expression, we isolated MASMCs from LPA receptor-knockout mice. Our results demonstrated that SMCs isolated from LPA receptor 1 (LPA1)-deficient mice completely lost responsiveness to LPA stimulation, which mediates induction of TF expression and activation of PKD and p38/JNK MAPK, indicating that LPA1 is responsible for PKD2-mediated activation of JNK2 and p38α. Taken together, our data reveal a new signaling mechanism in which the LPA1-PKD2 axis mediates LPA-induced TF expression via the p38α and JNK2 pathways. This finding provides new insights into LPA signaling, the PKD2 pathway, and the mechanisms of coagulation/atherothrombosis.


Assuntos
Aorta/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Canais de Cátion TRPP/metabolismo , Animais , Ativação Enzimática , Lisofosfolipídeos/metabolismo , Camundongos
7.
Am J Physiol Heart Circ Physiol ; 321(4): H756-H769, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506228

RESUMO

Inflammation caused by infiltrating macrophages and T cells promotes plaque growth in atherosclerosis. Cadherin-11 (CDH11) is a cell-cell adhesion protein implicated in several fibrotic and inflammatory diseases. Much of the research on CDH11 concerns its role in fibroblasts, although its expression in immune cells has been noted as well. The objective of this study was to assess the effect of CDH11 on the atherosclerotic immune response. In vivo studies of atherosclerosis indicated an increase in Cdh11 in plaque tissue. However, global loss of Cdh11 resulted in increased atherosclerosis and inflammation. It also altered the immune response in circulating leukocytes, decreasing myeloid cell populations and increasing T-cell populations, suggesting possible impaired myeloid migration. Bone marrow transplants from Cdh11-deficient mice resulted in similar immune cell profiles. In vitro examination of Cdh11-/- macrophages revealed reduced migration, despite upregulation of a number of genes related to locomotion. Flow cytometry revealed an increase in CD3+ and CD4+ helper T-cell populations in the blood of both the global Cdh11 loss and the bone marrow transplant animals, possibly resulting from increased expression by Cdh11-/- macrophages of major histocompatibility complex class II molecule genes, which bind to CD4+ T cells for coordinated activation. CDH11 fundamentally alters the immune response in atherosclerosis, resulting in part from impaired macrophage migration and altered macrophage-induced T-cell activation.NEW & NOTEWORTHY Cadherin-11 is well known to contribute to inflammatory and fibrotic disease. Here, we examined its role in atherosclerosis progression, which is predominantly an inflammatory process. We found that while cadherin-11 is associated with plaque progression, global loss of cadherin-11 exacerbated the disease phenotype. Moreover, loss of cadherin-11 in bone marrow-derived immune cells resulted in impaired macrophage migration and an unexplained increase in circulating helper T cells, presumably due to altered macrophage function without cadherin-11.


Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Caderinas/deficiência , Quimiotaxia , Macrófagos/metabolismo , Placa Aterosclerótica , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Transplante de Medula Óssea , Caderinas/genética , Modelos Animais de Doenças , Feminino , Ativação Linfocitária , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia
8.
FASEB J ; 35(9): e21831, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383982

RESUMO

The nuclear factor of activated T-cells 5 (NFAT5) is a transcriptional regulator of macrophage activation and T-cell development, which controls stabilizing responses of cells to hypertonic and biomechanical stress. In this study, we detected NFAT5 in the media layer of arteries adjacent to human arteriosclerotic plaques and analyzed its role in vascular smooth muscle cells (VSMCs) known to contribute to arteriosclerosis through the uptake of lipids and transformation into foam cells. Exposure of both human and mouse VSMCs to cholesterol stimulated the nuclear translocation of NFAT5 and increased the expression of the ATP-binding cassette transporter Abca1, required to regulate cholesterol efflux from cells. Loss of Nfat5 promoted cholesterol accumulation in these cells and inhibited the expression of genes involved in the management of oxidative stress or lipid handling, such as Sod1, Plin2, Fabp3, and Ppard. The functional relevance of these observations was subsequently investigated in mice fed a high-fat diet upon induction of a smooth muscle cell-specific genetic ablation of Nfat5 (Nfat5(SMC)-/- ). Under these conditions, Nfat5(SMC)-/- but not Nfat5fl/fl mice developed small, focal lipid-rich lesions in the aorta after 14 and 25 weeks, which were formed by intracellular lipid droplets deposited in the sub-intimal VSMCs layer. While known for being activated by external stimuli, NFAT5 was found to mediate the expression of VSMC genes associated with the handling of lipids in response to a cholesterol-rich environment. Failure of this protective function may promote the formation of lipid-laden arterial VSMCs and pro-atherogenic vascular responses.


Assuntos
Aorta/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Idoso , Animais , Aterosclerose/metabolismo , Células Cultivadas , Colesterol/metabolismo , Feminino , Células Espumosas/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Hipercolesterolemia/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Túnica Íntima/metabolismo
9.
Arch Biochem Biophys ; 710: 109000, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343486

RESUMO

Impaired endothelium-mediated vasodilation and/or increased sensitivity to vasoconstrictors lead to vascular smooth muscle cell (VSMC) dysfunction in individuals with diabetes. Diabetic nephropathy is associated with a considerably higher risk of cardiovascular disease and death than their nondiabetic counterparts. We studied the activity of Cullin 3 RING ubiquitin ligase (CRL3) and its substrates in mice using an intraperitoneal injection of streptozotocin (STZ) and db/db mice. The levels of CRL3 adaptors, including Kelch-like 2/3 (KLHL2/3) and Rho-related BTB domain-containing protein 1, were significantly decreased in the aortic tissues and heart of the STZ group, whereas the levels of Cullin 3 (CUL3) and its neddylated derivatives were substantially increased. Decreased KLHL3 expression and significantly increased expression of NEDD8 conjugates were observed in the kidneys of db/db mice. The neddylation inhibitor MLN4924 decreased the degradation of KLHL2/KLHL3 under high-glucose conditions with/without insulin, and transfection with KLHL2 promoted the degradation of its substrates with-no-lysine (WNK) kinases. Increased abundance of WNK3, RhoA/ROCK activity and phosphodiesterase 5 enhanced the sensibility to vasoconstrictors and impaired vasodilation. Moreover, WNK3 localized in VSMCs undergoing cell division, and high-glucose medium increased WNK3 signaling in VSMCs undergoing mitosis, which might explain the increased thickness of aortic tissues in subjects with diabetes. Increases in WNK4 abundance resulted in increased sodium reabsorption in the distal renal tubules. Thus, KLHL2/RhoBTB1/KLHL3 inactivation in the aortic tissues and kidney is a result of excessive activation of neddylation in hyperglycemia and hyperinsulinemia, which affects vascular tone and sodium reabsorption.


Assuntos
Proteínas Culina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Sódio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Vasoconstrição/fisiologia , Animais , Aorta/metabolismo , Aorta/patologia , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
10.
Nutrients ; 13(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445015

RESUMO

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg-1 aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H2O2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.


Assuntos
Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Arecaceae , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vasodilatação/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Antioxidantes/isolamento & purificação , Aorta/metabolismo , Aorta/fisiopatologia , Arecaceae/química , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Frutas , Humanos , Hipoglicemiantes/isolamento & purificação , Lipídeos/sangue , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Ratos Wistar
11.
Life Sci ; 283: 119868, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34358551

RESUMO

AIMS: In this study, we investigated the vasodilatory effects of trelagliptin (a dipeptidyl peptidase-4 inhibitor) and its related mechanisms using rabbit aortic rings. MAIN METHODS: Arterial tone measurement was performed in rabbit thoracic aortic rings. KEY FINDINGS: Trelagliptin induced vasodilation in a dose-dependent manner. Pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide, large-conductance Ca2+-activated K+ channel inhibitor paxilline, and inwardly rectifying K+ channel inhibitor Ba2+ did not affect the vasodilatory effect of trelagliptin. However, pretreatment with the voltage-dependent K+ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly attenuated the vasodilatory effect of trelagliptin, suggesting that the vasodilatory effect of trelagliptin is associated with Kv channel activation. Although pretreatment with Kv1.5 and Kv2.1 subtype inhibitors did not affect the response to trelagliptin, pretreatment with a Kv7.X subtype inhibitor effectively reduced the vasodilatory effect of trelagliptin. Furthermore, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors also significantly attenuated the vasodilatory effect of trelagliptin. These effects, however, were not affected by pretreatment with Ca2+ channel inhibitors, adenylyl cyclase/PKA inhibitors, guanylyl cyclase/PKG inhibitors, or removal of the endothelium. SIGNIFICANCE: From these results, we concluded that the vasodilatory effect of trelagliptin was associated with the activation of Kv channels (primary the Kv7.X subtype) and SERCA pump regardless of other K+ channels, Ca2+ channels, cAMP/PKA-related or cGMP/PKG-related signaling pathways, and the endothelium. Therefore, caution is required when prescribing trelagliptin to the patients with hypotension and diabetes.


Assuntos
Aorta/metabolismo , Endotélio Vascular/metabolismo , Hipoglicemiantes/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Uracila/análogos & derivados , Vasodilatação/efeitos dos fármacos , Animais , Masculino , Coelhos , Uracila/farmacologia
12.
Biochem Pharmacol ; 192: 114738, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418354

RESUMO

The renin-angiotensin system, with the octapeptide angiotensin II as key player, is important in the renal, cardiac and vascular physiology. Prolyl carboxypeptidase (PRCP), prolyl endopeptidase (PREP) and angiotensin converting enzyme 2 (ACE2) are reported to be involved in the conversion of angiotensin II to angiotensin (1-7). Previous investigations showed that the processing of angiotensin II is cell- and species-specific and little is known about its conversion in human endothelial cells. Therefore, we aimed to investigate the C-terminal processing of angiotensin II and III in comparison to the processing of des-Arg9-bradykinin in human endothelial cells. To this end, human umbilical vein and aortic endothelial cells (HUVEC and HAoEC) were incubated with the peptides for different time periods. Mass spectrometry analysis was performed on the supernatants to check for cleavage products. Contribution of PRCP, ACE2 and PREP to the peptide cleavage was evaluated by use of the selective inhibitors compound 8o, DX600 and KYP-2047. The use of these selective inhibitors revealed that the C-terminal cleavage of angiotensin II and III was PRCP-dependent in HUVEC and HAoEC. In contrast, the C-terminal cleavage of des-Arg9-bradykinin was PRCP-dependent in HUVEC and PRCP- and ACE2-dependent in HAoEC. With this study, we contribute to a better understanding of the processing of peptides involved in the alternative renin-angiotensin system. We conclude that PRCP is the main enzyme for the C-terminal processing of angiotensin peptides in human umbilical vein and aortic endothelial cells. For the first time the contribution of PRCP was investigated by use of a selective PRCP-inhibitor.


Assuntos
Angiotensina III/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Aorta/metabolismo , Carboxipeptidases/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Angiotensina III/antagonistas & inibidores , Aorta/citologia , Aorta/efeitos dos fármacos , Carboxipeptidases/antagonistas & inibidores , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Peptídeos/farmacologia
13.
Arch Biochem Biophys ; 711: 109007, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34400144

RESUMO

Pituitary tumor-transforming gene 1 (PTTG1) has been found to be associated with the process of cell proliferation and invasion, and is highly expressed in aortic dissection (AD). However, its potential role and underlying mechanism in AD remain uncertain. This study aims at elucidating the roles of specificity protein 1 (SP1) and PTTG1 in the migration and phenotypic switching of aortic vascular smooth muscle cells (VSMCs) in AD. Aortic samples were collected from 35 patients with AD for examination of PTTG1 expression in the tissues by qPCR, western blot and immunofluorescence. Human aortic vascular smooth muscle cells (HAVSMCs) were stimulated with platelet-derived growth factor-BB (PDGF-BB) to establish the cellular model of AD. PTTG1 expression in VSMCs was also examined by qPCR and western blot. Cell viability was detected by CCK-8, cell proliferation by EdU staining and cell migration by wound healing and transwell. Western blot was then performed to assay migration-related proteins. After interference with PTTG1, the levels of smooth muscle pthenotypic switch markers smooth muscle protein 22 alpha (SM22-α) and osteopontin (OPN) were detected by qPCR, western blot and immunofluorescence. The binding of SP1 and PTTG1 was verified with dual-luciferase reporter assay and chromatin immunoprecipitation assay (ChIP). PTTG1 overexpression was found in AD patients. Interference with PTTG1 attenuated the proliferation and migration of PDGF-BB-stimulated HAVSMCs, in addition to their switching from contractile phenotype to synthetic phenotype. Transcription factor SP1 was up-regulated in PDGF-BB-stimulated HAVSMCs, combined with PTTG1 promoter sequence and regulated PTTG1 expression, whose overexpression reversed the effects of PTTG1 interference on cell proliferation, migration and phenotypic switching. SP1 transcriptional activation of PTTG1 activated MAPK/ERK signaling pathway. In conclusion, SP1 transcriptional activation of PTTG1 regulates the migration and phenotypic transformation of HAVSMCs in AD by MAPK Signaling.


Assuntos
Aneurisma Dissecante/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Securina/metabolismo , Fator de Transcrição Sp1/metabolismo , Aorta/metabolismo , Becaplermina/farmacologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Securina/genética , Ativação Transcricional/fisiologia , Regulação para Cima/efeitos dos fármacos
14.
Am J Physiol Heart Circ Physiol ; 321(4): H667-H683, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415187

RESUMO

Airborne particulate matter (PM) is associated with an increased risk for cardiovascular diseases. Although the goal of thermal remediation is to eliminate organic wastes through combustion, when incomplete combustion occurs, organics chemisorb to transition metals to generate PM-containing environmentally persistent free radicals (EPFRs). Similar EPFR species have been detected in PM found in diesel and gasoline exhaust, woodsmoke, and urban air. Prior in vivo studies demonstrated that EPFRs reduce cardiac function secondary to elevations in pulmonary arterial pressures. In vitro studies showed that EPFRs increase ROS and cytokines in pulmonary epithelial cells. We thus hypothesized that EPFR inhalation would promote lung inflammation and oxidative stress, leading to systemic inflammation, vascular endothelial injury, and a decline in vascular function. Mice were exposed to EPFRs for either 4 h or for 4 h/day for 10 days and lung and vascular function were assessed. After a 4-h exposure, plasma nitric oxide (NO) was reduced while endothelin-1 (ET-1) was increased, however lung function was not altered. After 10 day, plasma NO and ET-1 levels were again altered and lung tidal volume was reduced. These time course studies suggested the vasculature may be an early target of injury. To test this hypothesis, an intermediate time point of 3 days was selected. Though the mice exhibited no marked inflammation in either the lung or the blood, we did note significantly reduced endothelial function concurrent with a reduction in lung tidal volume and an elevation in annexin V protein levels in the lung. Although vascular dysfunction was not dependent upon inflammation, it may be associated with an injury at the air-blood interface. Gene expression analysis suggested roles for oxidative stress and aryl hydrocarbon receptor (Ahr) signaling. Studies probing the relationship between pulmonary oxidative stress and AhR signaling at the air-blood interface with vascular dysfunction seem warranted.NEW & NOTEWORTHY Particulate matter (PM) resulting from the combustion of organic matter is known to contribute to cardiopulmonary disease. Despite hypotheses that cardiovascular dysfunction occurring after PM exposures is secondary to lung or systemic inflammation, these studies investigating exposures to PM-containing environmentally persistent free radicals (EPFRs) demonstrate that cardiovascular dysfunction precedes pulmonary inflammation. The cardiopulmonary health consequences of EPFRs have yet to be thoroughly evaluated, especially in healthy, adult mice. Our data suggest the vasculature as a direct target of PM exposure, and our studies aimed to elucidate the mechanisms contributing to EPFR-induced vascular dysfunction.


Assuntos
Aorta/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Endotélio Vascular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Radicais Livres/toxicidade , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Pneumonia/induzido quimicamente , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Relação Dose-Resposta a Droga , Endotelina-1/sangue , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Regulação da Expressão Gênica , Exposição por Inalação , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/sangue , Estresse Oxidativo , Pneumonia/genética , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Volume de Ventilação Pulmonar/efeitos dos fármacos , Fatores de Tempo
15.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299243

RESUMO

(1) Background: The aim of the present study was the biocompatibility analysis of a novel xenogeneic vascular graft material (PAP) based on native collagen won from porcine aorta using the subcutaneous implantation model up to 120 days post implantationem. As a control, an already commercially available collagen-based vessel graft (XenoSure®) based on bovine pericardium was used. Another focus was to analyze the (ultra-) structure and the purification effort. (2) Methods: Established methodologies such as the histological material analysis and the conduct of the subcutaneous implantation model in Wistar rats were applied. Moreover, established methods combining histological, immunohistochemical, and histomorphometrical procedures were applied to analyze the tissue reactions to the vessel graft materials, including the induction of pro- and anti-inflammatory macrophages to test the immune response. (3) Results: The results showed that the PAP implants induced a special cellular infiltration and host tissue integration based on its three different parts based on the different layers of the donor tissue. Thereby, these material parts induced a vascularization pattern that branches to all parts of the graft and altogether a balanced immune tissue reaction in contrast to the control material. (4) Conclusions: PAP implants seemed to be advantageous in many aspects: (i) cellular infiltration and host tissue integration, (ii) vascularization pattern that branches to all parts of the graft, and (iii) balanced immune tissue reaction that can result in less scar tissue and enhanced integrative healing patterns. Moreover, the unique trans-implant vascularization can provide unprecedented anti-infection properties that can avoid material-related bacterial infections.


Assuntos
Prótese Vascular/veterinária , Transplante de Tecidos/métodos , Animais , Aorta/metabolismo , Aorta/transplante , Materiais Biocompatíveis/metabolismo , Bioprótese , Bovinos , Colágeno/metabolismo , Xenoenxertos/metabolismo , Xenoenxertos/fisiologia , Ratos , Ratos Wistar , Suínos/metabolismo , Imunologia de Transplantes/imunologia , Cicatrização/fisiologia
16.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34265237

RESUMO

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


Assuntos
Aneurisma da Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Locos de Características Quantitativas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Estudos de Casos e Controles , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
17.
Molecules ; 26(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299486

RESUMO

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.


Assuntos
Berberina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Berberina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/metabolismo
18.
Biomolecules ; 11(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202347

RESUMO

Atherosclerosis is a multifactorial disease, for which the etiology is so complex that we are currently unable to prevent it and effectively lower the statistics on mortality from cardiovascular diseases. Parallel to modern analyses in molecular biology and biochemistry, we want to carry out analyses at the level of micro- and macroelements in order to discover the interdependencies between elements during atherogenesis. In this work, we used the Inductively Coupled Plasma Optical Emission Spectrometer (ICP-OES) to determine the content of calcium, magnesium, iron, copper, chromium, zinc, manganese, cadmium, lead, and zinc in the aorta sections of people who died a sudden death. We also estimated the content of metalloenzymes MMP-9, NOS-3, and SOD-2 using the immunohistochemical method. It was observed that with the age of the patient, the calcium content of the artery increased, while the content of copper and iron decreased. Very high correlations (correlation coefficient above 0.8) were observed for pairs of parameters in women: Mn-Ca, Fe-Cu, and Ca-Cd, and in men: Mn-Zn. The degree of atherosclerosis negatively correlated with magnesium and with cadmium. Chromium inhibited absorption of essential trace elements such as Cu and Fe due to its content being above the quantification threshold only if Cu and Fe were lower. Moreover, we discussed how to design research for the future in order to learn more about the pathomechanism of atherosclerosis and the effect of taking dietary supplements on the prevalence of cardiovascular diseases.


Assuntos
Aorta/química , Aorta/metabolismo , Aterosclerose/metabolismo , Espectrofotometria Atômica/métodos , Oligoelementos/análise , Oligoelementos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Aorta/patologia , Aterosclerose/patologia , Cádmio/análise , Cádmio/metabolismo , Cálcio/análise , Cálcio/metabolismo , Cobre/análise , Cobre/metabolismo , Feminino , Humanos , Ferro/análise , Ferro/metabolismo , Magnésio/análise , Magnésio/metabolismo , Masculino , Manganês/análise , Manganês/metabolismo , Pessoa de Meia-Idade
19.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281165

RESUMO

Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.


Assuntos
Aneurisma da Aorta Torácica/genética , Proteína-Lisina 6-Oxidase/genética , Adulto , Aneurisma Dissecante/genética , Aneurisma Dissecante/fisiopatologia , Aorta/metabolismo , Aneurisma da Aorta Torácica/fisiopatologia , Artérias/metabolismo , Tecido Conjuntivo/metabolismo , Doenças do Tecido Conjuntivo/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Proteína-Lisina 6-Oxidase/metabolismo
20.
Am J Physiol Cell Physiol ; 321(3): C535-C548, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288724

RESUMO

Extracellular vesicles (EVs) contain biological molecules and are secreted by cells into the extracellular milieu. The endothelial sodium channel (EnNaC) plays an important role in modulating endothelial cell stiffness. We hypothesized EVs secreted from human aortic endothelial cells (hAoECs) positively regulate EnNaC in an autocrine-dependent manner. A comprehensive lipidomic analysis using targeted mass spectrometry was performed on multiple preparations of EVs isolated from the conditioned media of hAoECs or complete growth media of these cells. Cultured hAoECs challenged with EVs isolated from the conditioned media of these cells resulted in an increase in EnNaC activity when compared with the same concentration of media-derived EVs or vehicle alone. EVs isolated from the conditioned media of hAoECs but not human fibroblast cells were enriched in MARCKS-like protein 1 (MLP1). The pharmacological inhibition of the negative regulator of MLP1, protein kinase C, in cultured hAoECs resulted in an increase in EV size and release compared with vehicle or pharmacological inhibition of protein kinase D. The MLP1-enriched EVs increased the density of actin filaments in cultured hAoECs compared with EVs isolated from human fibroblast cells lacking MLP1. We quantified 141 lipids from glycerolipids, glycerophospholipids, and sphingolipids in conditioned media EVs that represented twice the number found in control media EVs. The concentrations of sphingomyelin, lysophosphatidylcholine and phosphatidylethanolamine were higher in conditioned media EVs. These results provide the first evidence for EnNaC regulation in hAoECs by EVs and provide insight into a possible mechanism involving MLP1, unsaturated lipids, and bioactive lipids.


Assuntos
Proteínas de Ligação a Calmodulina/genética , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Lisofosfatidilcolinas/metabolismo , Proteínas dos Microfilamentos/genética , Fosfatidiletanolaminas/metabolismo , Esfingomielinas/metabolismo , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Aorta/citologia , Aorta/metabolismo , Comunicação Autócrina , Proteínas de Ligação a Calmodulina/metabolismo , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Vesículas Extracelulares/química , Expressão Gênica , Glicerofosfolipídeos/metabolismo , Humanos , Lipidômica/métodos , Lisofosfatidilcolinas/farmacologia , Proteínas dos Microfilamentos/metabolismo , Fosfatidiletanolaminas/farmacologia , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Esfingomielinas/farmacologia
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