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1.
Redox Biol ; 32: 101493, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32182574

RESUMO

Nitroxyl (HNO), one-electron reduced and protonated sibling of nitric oxide (NO), is a potential regulator of cardiovascular functions. It produces positive inotropic, lusitropic, myocardial anti-hypertrophic and vasodilator properties. Despite of these favorable actions, the significance and the possible mechanisms of HNO in diabetic hearts have yet to be fully elucidated. H9c2 cells or primary neonatal mouse cardiomyocytes were incubated with normal glucose (NG) or high glucose (HG). Male C57BL/6 mice received intraperitoneal injection of streptozotocin (STZ) to induce diabetes. Here, we demonstrated that the baseline fluorescence signals of HNO in H9c2 cells were reinforced by both HNO donor Angeli's salt (AS), and the mixture of hydrogen sulfide (H2S) donor sodium hydrogen sulfide (NaHS) and NO donor sodium nitroprusside (SNP), but decreased by HG. Pretreatment with AS significantly reduced HG-induced cell vitality injury, apoptosis, reactive oxygen species (ROS) generation, and hypertrophy in H9c2 cells. This effect was mediated by induction of caveolin-3 (Cav-3)/endothelial nitric oxide (NO) synthase (eNOS) complex. Disruption of Cav-3/eNOS by pharmacological manipulation or small interfering RNA (siRNA) abolished the protective effects of AS in HG-incubated H9c2 cells. In STZ-induced diabetic mice, administration of AS ameliorated the development of diabetic cardiomyopathy, as evidenced by improved cardiac function and reduced cardiac hypertrophy, apoptosis, oxidative stress and myocardial fibrosis without affecting hyperglycemia. This study shed light on how interaction of NO and H2S regulates cardiac pathology and provide new route to treat diabetic cardiomyopathy with HNO.

2.
Antioxid Redox Signal ; 32(5): 331-349, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31617376

RESUMO

Significance: As one-electron reduced molecule of nitric oxide (NO), nitroxyl (HNO) has gained enormous attention because of its novel physiological or pharmacological properties, ranging from cardiovascular protective actions to antitumoricidal effects. Recent Advances: HNO is emerging as a new entity with therapeutic advantages over its redox sibling, NO. The interests in the chemical, pharmacological, and biological characteristics of HNO have broadened our current understanding of its role in physiology and pathophysiology. Critical Issues: In particular, the experimental evidence suggests the therapeutic potential of HNO in tumor pharmacology, such as neuroblastoma, gastrointestinal tumor, ovarian, lung, and breast cancers. Indeed, HNO donors have been demonstrated to attenuate tumor proliferation and angiogenesis. Future Directions: In this review, the generation and detection of HNO are outlined, and the roles of HNO in cancer progression are further discussed. We anticipate that the completion of this review might give novel insights into the roles of HNO in cancer pharmacology and open up a novel field of cancer therapy based on HNO.

3.
Redox Biol ; 30: 101411, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31884071

RESUMO

Salusin-ß is abundantly expressed in many organs and tissues including heart, blood vessels, brain and kidneys. Recent studies have identified salusin-ß as a bioactive peptide that contributes to various diseases, such as atherosclerosis, hypertension, diabetes and metabolic syndrome. However, the role of salusin-ß in the pathogenesis of acute kidney injury (AKI) is largely unclear. In the present study, we investigated the roles of salusin-ß in cisplatin or lipopolysaccharide (LPS)-induced renal injury. Herein, we found that salusin-ß expression was upregulated in both renal tubular cells and kidney tissues induced by both cisplatin and LPS. In vitro, silencing of salusin-ß diminished, whereas overexpression of salusin-ß exaggerated the increased PKC phosphorylation, oxidative stress, histone γH2AX expression, p53 activation and apoptosis in either cisplatin or LPS-challenged renal tubular cells. More importantly, salusin-ß overexpression-induced tubular cell apoptosis were abolished by using the PKC inhibitor Go 6976, reactive oxygen species (ROS) scavenger NAC, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (Apo) or p53 inhibitor Pifithrin-α. In animals, blockade of salusin-ß alleviated PKC phosphorylation, ROS accumulation, DNA damage, and p53 activation as well as renal dysfunction in mice after administration of cisplatin or LPS. Taken together, these results suggest that overexpressed salusin-ß is deleterious in AKI by activation of the PKC/ROS signaling pathway, thereby priming renal tubular cells for apoptosis and death.

4.
Am J Transl Res ; 11(11): 7115-7125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814914

RESUMO

Circular RNAs (circRNAs) are potential biomarkers and therapeutic targets of coronary artery disease due to their high stability, covalently closed structure. And implied roles in gene regulation. The aim of this study was to identify and characterize circRNAs from human coronary arteries. Epicardial coronary arteries were removed during the autopsy of an 81-year-old man who died from heart attack. The natural history and histological classification of atherosclerotic lesions in coronary artery segments were analyzed by hematoxylin and eosin staining, and their circRNA expression profiles were characterized by RNA sequencing. RNA sequencing identified 1259 annotated and 381 novel circRNAs. Combined with the results of histologic examination, intersection analysis identified 54 upregulated and 12 downregulated circRNAs, representing 4.0% of the total number. Coronary artery segments with or without severe atherosclerosis showed distinctly different circRNA profiles on the basis of hierarchical clustering. Our results suggest that these 66 circRNAs contribute to the pathology underlying coronary artery atherosclerosis and may serve as diagnostic or therapeutic targets in coronary artery disease.

5.
Oxid Med Cell Longev ; 2019: 4616034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31636805

RESUMO

Activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of cardiovascular diseases. Sodium potassium ATPase (NKA) expression and activity are often regulated by angiotensin II (Ang II). This study is aimed at investigating whether DR-Ab, an antibody against 4th extracellular region of NKA, can protect Ang II-induced cardiomyocyte hypertrophy. Our results showed that Ang II treatment significantly reduced NKA activity and membrane expression. Pretreatment with DR-Ab preserved cell size in Ang II-induced cardiomyopathy by stabilizing the plasma membrane expression of NKA and restoring its activity. DR-Ab reduced intracellular ROS generation through inhibition of NADPH oxidase activity and protection of mitochondrial functions in Ang II-treated H9c2 cardiomyocytes. Pharmacological manipulation and Western blotting analysis demonstrated the cardioprotective effects were mediated by the activation of the AMPK/Sirt-3/PPARγ signaling pathway. Taken together, our results suggest that dysfunction of NKA is an important mechanism for Ang II-induced cardiomyopathy and DR-Ab may be a novel and promising therapeutic approach to treat cardiomyocyte hypertrophy.

6.
J Nutr Biochem ; 72: 108212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473513

RESUMO

Migration of vascular smooth muscle cell (VSMC) plays a critical role in the pathophysiology of hypertension and several other vascular diseases. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a bioactive constituent from Curcuma longa, is commonly used as a spice, food additive or dietary pigment. It has several health benefits including antioxidant, anti-inflammatory and anticancer properties. This study examined the roles of curcumin in VSMC migration in hypertension and underlying mechanism. VSMC was isolated and prepared from thoracic aorta of Wistar-Kyoto rats and spontaneously hypertensive rats (SHR). VSMC migration was evaluated with Boyden chamber assay and wound-healing assay. Curcumin attenuated VSMC migration, inhibited nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression and reduced interleukin (IL)-1ß concentration in VSMC of SHR, which were similar to the effects of NLRP3 knockdown on IL-1ß concentration and VSMC migration. Curcumin inhibited NFκB activation in VSMC of SHR, which was similar to the effects of NFκB inhibitor BAY11-7082 on NFκB activation. In another in vitro model of rat VSMC migration, curcumin also inhibited angiotensin II-induced VSMC migration, NFκB activation, NLRP3 expression and IL-1ß production. Intragastric administration of curcumin in SHR attenuated hypertension and reduced NFκB activation, NLRP3 and matrix metalloproteinase-9 expressions and aortic media thickness. These results indicate that curcumin inhibits VSMC migration via inhibiting NFκB-mediated NLRP3 expression in VSMC of SHR or in angiotensin II-treated VSMC. Curcumin attenuates hypertension, vascular inflammation and vascular remodeling in SHR.

7.
Molecules ; 24(15)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390847

RESUMO

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Fibrose , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Sistema Renina-Angiotensina
8.
Adv Exp Med Biol ; 1165: 37-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399960

RESUMO

Arterial hypertension remains to be a serious problem with considerable morbidity and mortality worldwide in the present age. Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, renal failure, and heart failure. Hypertensive nephropathy is the second leading cause of death in chronic kidney disease (CKD) around the world. Long-time hypertension loading results in renal interstitial fibrosis, which is associated with aberrant activation of renal fibroblasts and excessive generation of extracellular matrix (ECM) proteins. Increasing evidence supported that proteinuria, tubular hypertrophy, oxidative stress, activation of renin-aldosterone-angiotensin system (RAAS), collagen turnover, chronic inflammation, and vasoactive substances synergistically contributed to the pathogenesis of hypertensive renal fibrosis. However, the mechanisms involving the pathogenesis of hypertensive renal fibrosis are complex and not fully understood. Also, the effective clinical therapy to halt or even reverse renal fibrosis in hypertension is still limited. In this chapter, we aimed to provide an overview of the main pathophysiologic and mechanistic features of renal fibrosis under hypertensive state. The completion of the studies in these directions would improve our understanding of renal fibrosis in hypertension and also help us better screen treatment strategies for preventing renal destruction associated with hypertension.


Assuntos
Hipertensão/complicações , Nefropatias/complicações , Fibrose , Humanos , Hipertrofia , Rim/patologia , Estresse Oxidativo , Proteinúria , Sistema Renina-Angiotensina
9.
Eur J Pharmacol ; 852: 90-98, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851272

RESUMO

Vascular calcification (VC) is a critical feature of chronic kidney disease (CKD), diabetes, hypertension, and atherosclerosis. Death-associated protein kinase 3 (DAPK3) is involved in vascular remodeling in hypertension. However, it remains to be clarified whether DAPK3 controls vascular smooth muscle cell (VSMC) phenotypic transition into an osteogenic cell phenotype, which is an important process for VC. In vivo VC was induced in rats by vitamin D3 and nicotine. VSMCs were incubated with calcifying media containing ß-glycerophosphate and Ca2+ to induce VC in vitro. Herein, we demonstrated increased expression of DAPK3 in the aortas of VC rats and VSMCs cultured in calcifying media. Knockdown of DAPK3 significantly inhibited calcifying media-induced VSMC mineralization and retarded the phenotypic transformation of VSMCs into osteogenic cells. Silencing of DAPK3 suppressed endoplasmic reticulum stress (ERS) related protein expressions, but upregulated the phosphorylation level of AMP-activated protein kinase (AMPK) in calcified VSMCs. Moreover, pretreatment with AMPK inhibitor Compound C abolished DAPK3 shRNA-mediated inhibition of ERS in VSMCs. In vivo, DAPK inhibitor significantly prevented calcium deposition in the aortas of VC rats. The present results revealed that DAPK3 modulated VSMC calcification through AMPK-mediated ERS signaling.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Associadas com Morte Celular/deficiência , Proteínas Quinases Associadas com Morte Celular/genética , Estresse do Retículo Endoplasmático/genética , Técnicas de Silenciamento de Genes , Calcificação Vascular/patologia , Animais , Proteínas Quinases Associadas com Morte Celular/antagonistas & inibidores , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Músculo Liso Vascular/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
10.
Biomed Pharmacother ; 102: 711-717, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29604590

RESUMO

The dedifferentiation, proliferation and migration of vascular smooth muscle cells (VSMCs) are essential in the progression of hypertension, atherosclerosis and intimal hyperplasia. Nesfatin-1 is a potential modulator in cardiovascular functions. However, the role of nesfatin-1 in VSMC biology has not been explored. The present study was designed to determine the regulatory role of nesfatin-1 in VSMC proliferation, migration and intimal hyperplasia after vascular injury. Herein, we demonstrated that nesfatin-1 promoted VSMC phenotype switch from a contractile to a synthetic state, stimulated VSMC proliferation and migration in vitro. At the molecular level, nesfatin-1 upregulated the protein and mRNA levels, as well as the promoter activities of matrix metalloproteinase 2 (MMP-2) and MMP-9, but downregulated peroxisome proliferator-activated receptor γ (PPARγ) levels and promoter activity in VSMCs. Blockade of MMP-2/9 or activation of PPARγ prevented the nesfatin-1-induced VSMC proliferation and migration. In vivo, knockdown of nesfatin-1 ameliorated neointima formation following rat carotid injury. Taken together, our results indicated that nesfatin-1 stimulated VSMC proliferation, migration and neointimal hyperplasia by elevating MMP2/MMP-9 levels and inhibiting PPARγ gene expression.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Neointima/patologia , Proteínas do Tecido Nervoso/metabolismo , PPAR gama/metabolismo , Regulação para Cima , Animais , Desdiferenciação Celular , Movimento Celular , Proliferação de Células , Inativação Gênica , Hiperplasia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miócitos de Músculo Liso/enzimologia , Neointima/metabolismo , Ratos Sprague-Dawley
11.
Biochim Biophys Acta Mol Basis Dis ; 1864(6 Pt A): 2154-2168, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29627363

RESUMO

The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Proteínas de Ligação a DNA/fisiologia , Hipertensão/etiologia , Miócitos de Músculo Liso/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Remodelação Vascular/fisiologia , Animais , Aorta/citologia , Pressão Sanguínea/fisiologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Hipertensão/patologia , Masculino , Músculo Liso Vascular/citologia , Fenótipo , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de Sinais/fisiologia
12.
Asian J Androl ; 20(4): 355-359, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29516873

RESUMO

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.


Assuntos
Ejaculação/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Copulação , Feminino , Masculino , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Comportamento Sexual Animal/fisiologia , Nervos Esplâncnicos/citologia , Nervos Esplâncnicos/fisiologia
13.
Int Urol Nephrol ; 50(3): 559-570, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29094331

RESUMO

Chronic kidney disease causes uremia-related endothelial cell dysfunction associated with high risk for cardiovascular diseases. The vascular endothelium is permanently exposed to uraemic toxins including indoxyl sulfate, which provokes endothelial damage in subjects with end-stage renal disease. Pterostilbene (PT) is identified to be homologous derivative of resveratrol and exerts antioxidant and anti-inflammatory actions. However, the effects of PT on uraemic serum-induced endothelial cell damage have not been elucidated. In this study, we investigated the effects and mechanisms of PT on uraemic serum (US)-mediated injury in human umbilical vein endothelial cells (HUVECs). Treatment of US obviously reduced cell viability, inhibited superoxide dismutase activity and catalase activity, suppressed phosphorylated endothelial nitric oxide synthase (eNOS) protein level and eNOS activity, whereas promoted lactate dehydrogenase leakage, increased malondialdehyde, hydrogen peroxide, superoxide anions levels and NAD(P)H activity accompanied with increased nitrative stress and inflammatory response in HUVECs, and these changes were reversed after PT treatment. Under US environment, PT downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) protein levels. Of note, the level of HO-1 was decreased after the transfection of cells with Nrf2-siRNA, and HO-1 inhibitor Snpp abolished the protective effects of PT on HUVECs in response to US. Collectively, our study demonstrated that PT is effective in reducing US-evoked endothelial cell dysfunction via suppression of oxidative/nitrative stress and inflammatory response, which at least partly depended on Keap1/Nrf2/HO-1 signaling pathway.


Assuntos
Antioxidantes/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Soro , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Uremia/sangue , Adulto , Idoso , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Expressão Gênica , Heme Oxigenase-1/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Metaloporfirinas/farmacologia , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Protoporfirinas/farmacologia , RNA Interferente Pequeno/farmacologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Superóxido Dismutase/metabolismo , Uremia/etiologia
14.
Redox Biol ; 14: 656-668, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29175753

RESUMO

Phenotypic switch of vascular smooth muscle cells (VSMCs) is characterized by increased expressions of VSMC synthetic markers and decreased levels of VSMC contractile markers, which is an important step for VSMC proliferation and migration during the development and progression of cardiovascular diseases including atherosclerosis. Chicoric acid (CA) is identified to exert powerful cardiovascular protective effects. However, little is known about the effects of CA on VSMC biology. Herein, in cultured VSMCs, we showed that pretreatment with CA dose-dependently suppressed platelet-derived growth factor type BB (PDGF-BB)-induced VSMC phenotypic alteration, proliferation and migration. Mechanistically, PDGF-BB-treated VSMCs exhibited higher mammalian target of rapamycin (mTOR) and P70S6K phosphorylation, which was attenuated by CA pretreatment, diphenyleneiodonium chloride (DPI), reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) and nuclear factor-κB (NFκB) inhibitor Bay117082. PDGF-BB-triggered ROS production and p65-NFκB activation were inhibited by CA. In addition, both NAC and DPI abolished PDGF-BB-evoked p65-NFκB nuclear translocation, phosphorylation and degradation of Inhibitor κBα (IκBα). Of note, blockade of ROS/NFκB/mTOR/P70S6K signaling cascade prevented PDGF-BB-evoked VSMC phenotypic transformation, proliferation and migration. CA treatment prevented intimal hyperplasia and vascular remodeling in rat models of carotid artery ligation in vivo. These results suggest that CA impedes PDGF-BB-induced VSMC phenotypic switching, proliferation, migration and neointima formation via inhibition of ROS/NFκB/mTOR/P70S6K signaling cascade.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Desdiferenciação Celular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-sis/metabolismo , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Animais , Becaplermina , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
Int J Mol Sci ; 19(1)2017 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-29280941

RESUMO

This study was conducted to explore the hypothesis that the endogenous superoxide anions (O2-) and nitric oxide (NO) system of the paraventricular nucleus (PVN) regulates the cardiac sympathetic afferent reflex (CSAR) contributing to sympathoexcitation in obese rats induced by a high-fat diet (42% kcal as fat) for 12 weeks. CSAR was evaluated by monitoring the changes of renal sympathetic nerve activity (RSNA) and the mean arterial pressure (MAP) responses to the epicardial application of capsaicin (CAP) in anaesthetized rats. In obese rats with hypertension (OH group) or without hypertension (OB group), the levels of PVN O2-, angiotensinII (Ang II), Ang II type 1 receptor (AT1R), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were elevated, whereas neural NO synthase (nNOS) and NO were significantly reduced. Moreover, CSAR was markedly enhanced, which promoted the elevation of plasma norepinephrine levels. The enhanced CSAR was attenuated by PVN application of the superoxide scavenger polyethylene glycol-superoxide dismutase (PEG-SOD) and the NO donor sodium nitroprusside (SNP), and was strengthened by the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC) and the nNOS inhibitor N(ω)-propyl-l-arginine hydrochloride (PLA); conversely, there was a smaller CSAR response to PLA or SNP in rats that received a low-fat (12% kcal) diet. Furthermore, PVN pretreatment with the AT1R antagonist losartan or with PEG-SOD, but not SNP, abolished Ang II-induced CSAR enhancement. These findings suggest that obesity alters the PVN O2- and NO system that modulates CSAR and promotes sympathoexcitation.


Assuntos
Coração/fisiopatologia , Óxido Nítrico/metabolismo , Obesidade/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Reflexo , Superóxidos/metabolismo , Animais , Pressão Sanguínea , Coração/inervação , Frequência Cardíaca , Masculino , Óxido Nítrico/análise , Obesidade/complicações , Obesidade/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxidos/análise , Sistema Nervoso Simpático/fisiopatologia
16.
Cell Physiol Biochem ; 44(6): 2269-2280, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29262411

RESUMO

BACKGROUND/AIMS: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. METHODS: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3-/- mice. RESULTS: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3-/- mice. CONCLUSIONS: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.


Assuntos
Angiotensina II/metabolismo , Deleção de Genes , Hipertensão/genética , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Remodelação Vascular , Animais , Pressão Sanguínea , Células Cultivadas , Hipertensão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
17.
Cell Death Dis ; 8(10): e3074, 2017 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-28981106

RESUMO

Inflammation is involved in pathogenesis of hypertension. NLRP3 inflammasome activation is a powerful mediator of inflammatory response via caspase-1 activation. The present study was designed to determine the roles and mechanisms of NLRP3 inflammasome in phenotypic modulation and proliferation of vascular smooth muscle cells (VSMCs) in hypertension. Experiments were conducted in spontaneously hypertensive rats (SHR) and primary aortic VSMCs. NLRP3 inflammasome activation was observed in the media of aorta in SHR and in the VSMCs from SHR. Knockdown of NLRP3 inhibited inflammasome activation, VSMC phenotypic transformation and proliferation in SHR-derived VSMCs. Increased NFκB activation, histone acetylation and histone acetyltransferase expression were observed in SHR-derived VSMCs and in media of aorta in SHR. Chromatin immunoprecipitation analysis revealed the increased histone acetylation, p65-NFκB and Pol II occupancy at the NLRP3 promoter in vivo and in vitro. Inhibition of NFκB with BAY11-7082 or inhibition of histone acetyltransferase with curcumin prevented the NLRP3 inflammasome activation, VSMC phenotype switching and proliferation in VSMCs from SHR. Moreover, curcumin repressed NFκB activation. Silencing of NLRP3 gene ameliorated hypertension, vascular remodeling, NLRP3 inflammasome activation and phenotype switching in the aorta of SHR. These results indicate that NLRP3 inflammasome activation response to histone acetylation and NFκB activation contributes to VSMC phenotype switching and proliferation and vascular remodeling in hypertension.


Assuntos
Proliferação de Células/genética , Hipertensão/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Angiotensina II/genética , Animais , Caspase 1/genética , Curcumina/administração & dosagem , Regulação da Expressão Gênica , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenótipo , Ratos , Ratos Endogâmicos SHR/genética , Ratos Endogâmicos SHR/metabolismo , Transdução de Sinais
18.
Immunol Res ; 65(5): 1046-1058, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28868583

RESUMO

The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl4)-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl4 was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbα. Microarray analysis revealed that the genes showing the most differential expression in response to CCl4-induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl4-induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbα axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Endotélio Vascular/metabolismo , Fator de von Willebrand/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Endotélio Vascular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrinogênio/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Transdução de Sinais , Transcriptoma , Fator de von Willebrand/genética
19.
Biomed Pharmacother ; 95: 144-152, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28841454

RESUMO

Angiogenesis is a complex physiological process involving the growth of new capillaries. The impaired angiogenesis plays important roles in chronic wounds and ischaemic heart disease. Fibroblast growth factor 2 (FGF-2) exerts pro-angiogenic actions via activation of fibroblast growth factor receptor 1 (FGFR-1). We have identified that vaccarin increased the angiogenic activity of endothelial cells. In this study, we investigated whether FGF-2-mediated FGFR1 signaling pathway participated in vaccarin-mediated neovascularization formation. Human microvascular endothelial cells (HMEC)-1 were incubated with various doses of vaccarin. Our results showed that vaccarin dose-dependently up-regulated FGF-2 levels and phosphorylation of FGFR-1. Neutralization of FGF-2 with anti-FGF-2 antibody also abolished the proliferation, migration and tube formation of HMEC-1 cells induced by vaccarin. Both FGFR-1 inhibitor SU5402 and FGFR-1 siRNA blocked vaccarin-induced cell cycle progression and angiogenesis. The mouse Matrigel model study further unveiled that vaccarin stimulated the neovascularization and microvessel density in vivo, which was prevented by FGFR-1 inhibitor SU5402. Taken together, our results demonstrated for the first time that vaccarin was a novel inducer for FGF-2 expression, followed by phosphorylation of FGFR-1 and subsequent angiogenic behaviors in endothelial cells. Vaccarin may be a promising candidate of angiogenesis activator for neurovascular repair or therapy.


Assuntos
Células Endoteliais/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Flavonoides/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Ciclo Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Colágeno , Combinação de Medicamentos , Fator 2 de Crescimento de Fibroblastos/genética , Flavonoides/química , Glicosídeos/administração & dosagem , Glicosídeos/química , Glicosídeos/metabolismo , Humanos , Laminina , Camundongos , Camundongos Endogâmicos ICR , Neovascularização Fisiológica , Proteoglicanas , Interferência de RNA , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais
20.
Biochem Biophys Res Commun ; 490(3): 629-635, 2017 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-28630004

RESUMO

Oxidized low-density lipoprotein (ox-LDL) is well known to disrupt normal functionality of endothelium, which plays a prominent role in endothelial dysfunction in many cardiovascular diseases. CO-releasing molecule 2 (CORM-2) is a promising candidate for treatment of cardiovascular diseases. However, it has not been defined whether CORM-2 might improve endothelial injury induced by ox-LDL. The present study was undertaken to determine the regulatory role of CORM-2 in cell injury of ox-LDL-treated human umbilical vein endothelial cells (HUVECs). Our results showed that ox-LDL inhibited the cell proliferation, but promoted apoptosis and release of cytochrome c (cytc) from mitochondrion into cytoplasm, stimulated the cleavage of caspase-3 and mitochondrial permeability transition pore (MPTP) opening. In addition, ox-LDL-incubated HUVECs exhibited excessive reactive oxygen species (ROS), increased protein levels of NADPH oxidase subunits p22phox, p47phox, NOX-2 and activation of Wnt/ß-catenin signaling pathway. However, pretreatment with CORM-2 significantly reduced cell apoptosis, release of cytc from mitochondrion into cytoplasm, MPTP opening and cleavage of caspase-3, suppressed the superoxide anion generation and Wnt/ß-catenin pathway activation in HUVECs response to ox-LDL. Collectively, we provide the evidence that CORM-2 attenuated ox-LDL-mediated endothelial apoptosis and oxidative stress by recovering the mitochondrial function and blocking Wnt/ß-catenin pathway.


Assuntos
Células Endoteliais/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Compostos Organometálicos/farmacologia , Substâncias Protetoras/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Citocromos c/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
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