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1.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

7.
Aging (Albany NY) ; 12(21): 22335-22349, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33154191

RESUMO

The development of atherosclerosis is accompanied by the functional deterioration of plaque cells, which leads to the escalation of endothelial inflammation, abnormal vascular smooth muscle cell phenotype switching and the accumulation of lipid-laden macrophages within vascular walls. Autophagy, a highly conserved homeostatic mechanism, is critical for the delivery of cytoplasmic substrates to lysosomes for degradation. Moderate levels of autophagy prevent atherosclerosis by safeguarding plaque cells against apoptosis, preventing inflammation, and limiting the lipid burden, whereas excessive autophagy exacerbates cell damage and inflammation and thereby accelerates the formation of atherosclerotic plaques. Increasing lines of evidence suggest that long noncoding RNAs can be either beneficial or detrimental to atherosclerosis development by regulating the autophagy level. This review summarizes the research progress related to 1) the significant role of autophagy in atherosclerosis and 2) the effects of the lncRNA-mediated modulation of autophagy on the plaque cell fate, inflammation levels, proliferative capacity, and cholesterol metabolism and subsequently on atherogenesis.


Assuntos
Artérias/metabolismo , Aterosclerose/metabolismo , Autofagia , Placa Aterosclerótica , RNA Longo não Codificante/metabolismo , Animais , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/terapia , Proteínas Relacionadas à Autofagia/metabolismo , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , RNA Longo não Codificante/genética , Transdução de Sinais
8.
Biosci Rep ; 40(11)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-32964914

RESUMO

AIM: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. METHODS: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination. RESULTS: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. CONCLUSION: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Benzopiranos/farmacologia , Cardiomegalia/prevenção & controle , Ativadores de Enzimas/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Animais , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Ativação Enzimática , Fibrose , Masculino , Camundongos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais
9.
Mol Med ; 26(1): 72, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698876

RESUMO

Atherosclerosis (AS) is widely accepted to be a multistep pathophysiological process associated with several other processes such as angiogenesis and inflammatory response. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs (more than 200 nucleotides in length) and can regulate gene expression at the transcriptional and post-transcriptional levels. Recent studies suggest that lncRNA-H19 plays important roles in the regulation of angiogenesis, adipocyte differentiation, lipid metabolism, inflammatory response, cellular proliferation and apoptosis. In this review, we primarily discuss the roles of lncRNA-H19 in atherosclerosis-related pathophysiological processes and the potential mechanisms by which lncRNA-H19 regulates the development of atherosclerosis, to help provide a better understanding of the biological functions of lncRNA-H19 in atherosclerosis.

10.
Life Sci ; 257: 118032, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621920

RESUMO

Diabetes mellitus is one of the major global health issues, which is closely related to metabolic dysfunction and the chronic inflammatory diseases. Multiple studies have demonstrated that serum bilirubin is negatively correlated with metabolic syndrome and associated inflammatory diseases, including atherosclerosis, hypertension, etc. However, the roles of bilirubin in metabolic syndrome and associated inflammatory diseases still remain unclear. Here, we explain the role of bilirubin in metabolic syndrome and chronic inflammatory diseases and its therapeutic potential. Understanding the role of bilirubin activities in diabetes may serve as a therapeutic target for the treatment of chronic inflammatory diseases in diabetic patients.


Assuntos
Bilirrubina/metabolismo , Bilirrubina/fisiologia , Síndrome Metabólica/metabolismo , Aterosclerose/sangue , Bilirrubina/sangue , Humanos , Hipertensão/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/imunologia
11.
Hypertension ; 76(3): 827-838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32683902

RESUMO

NOX5 (NADPH oxidase 5) is a homolog of the gp91phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca2+-sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and ß-MHC (ß-myosin heavy chain) and prohypertrophic genes (Nppa, Nppb, and Myh7) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca2+-regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.


Assuntos
Acetilcisteína/farmacologia , Cardiomegalia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NADPH Oxidase 5/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/farmacologia , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Sequestradores de Radicais Livres/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/metabolismo , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fagócitos/enzimologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasoconstritores/farmacologia , Miosinas Ventriculares/metabolismo
15.
Hypertension ; 75(2): 275-284, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31865799

RESUMO

Hypertension, a multifactorial disorder resulting from the interplay between genetic predisposition and environmental risk factors, affects ≈30% of adults. Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD), as an underestimated metabolic abnormality, is strongly associated with an increased risk of incident prehypertension and hypertension. However, the role of NAFLD in the development of hypertension is still obscure and is highly overlooked by the general public. Herein, we highlight the epidemiological evidence and putative mechanisms focusing on the emerging roles of NAFLD in hypertension, with the purpose of reinforcing the notion that NAFLD may serve as an independent risk factor and an important driving force in the development and progression of hypertension. Finally, we also briefly summarize the current potential treatments for NAFLD that might also be beneficial approaches against hypertension.


Assuntos
Hipertensão , Hepatopatia Gordurosa não Alcoólica , Pré-Hipertensão , Interação Gene-Ambiente , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Pré-Hipertensão/epidemiologia , Pré-Hipertensão/prevenção & controle , Saúde Pública , Fatores de Risco
17.
Aging (Albany NY) ; 11(23): 10992-11009, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31790366

RESUMO

Mangiferin has been identified as a potent cardioprotective factor that enhances high-density lipoprotein cholesterol levels in plasma. The aim of this study was to investigate the impact of mangiferin on macrophage cholesterol efflux and the development of atherosclerosis. The results showed that mangiferin injection significantly decreased atherosclerotic plaque size, and reduced plasma levels of low-density lipoprotein cholesterol, triglyceride, and total cholesterol in apoE knockout mice, whereas reverse cholesterol transport efficiency and high-density lipoprotein cholesterol levels were enhanced. In vitro study showed that mangiferin prevented lipid accumulation and promoted [3H]-cholesterol efflux from acetylated LDL-loaded RAW264.7 macrophages with an increase in the expression of ATP binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ). Moreover, transfection of PPARγ siRNA or LXRα siRNA markedly abolished the positive effects of mangiferin on ABCA1/G1 expression and cholesterol efflux. The opposite effects were observed after treatment with PPARγ agonist rosiglitazone or LXRα agonist T0901317. In conclusion, mangiferin may attenuate atherogenesis by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1/G1 pathway.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Aterosclerose/metabolismo , Colesterol/metabolismo , Macrófagos/efeitos dos fármacos , Xantonas/farmacologia , Animais , Aterosclerose/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Células RAW 264.7
19.
Hepatology ; 69(6): 2471-2488, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30748020

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic. A large and growing unmet therapeutic need has inspired numerous studies in the field. Integrating the published genomic data available in the Gene Expression Omnibus (GEO) with NAFLD samples from rodents, we discovered that interferon regulatory factor 6 (IRF6) is significantly downregulated in high-fat diet (HFD)-induced fatty liver. In the current study, we identified IRF6 in hepatocytes as a protective factor in liver steatosis (LS). During HFD challenge, hepatic Irf6 was suppressed by promoter hypermethylation. Severity of HFD-induced LS was exacerbated in hepatocyte-specific Irf6 knockout mice, whereas hepatocyte-specific transgenic mice overexpressing Irf6 (IRF6-HTG) exhibited alleviated steatosis and metabolic disorder in response to HFD feeding. Mechanistic studies in vitro demonstrated that hepatocyte IRF6 directly binds to the promoter of the peroxisome proliferator-activated receptor γ (PPARγ) gene and subsequently halts the transcription of Pparγ and its target genes (e.g., genes that regulate lipogenesis and lipid acid uptake) under physiological conditions. Conclusion: Irf6 is downregulated by promoter hypermethylation upon metabolic stimulus exposure, which fail to inhibit Pparγ and its targets, driving abnormalities of lipid metabolism.


Assuntos
Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR gama/genética , Animais , Metilação de DNA/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Hepatócitos/citologia , Humanos , Fatores Reguladores de Interferon/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Distribuição Aleatória , Sensibilidade e Especificidade
20.
Cytokine ; 122: 154385, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-29703573

RESUMO

OBJECTIVE: Previous studies suggest that IL-8 has an important role in the regulation of cholesterol efflux, but whether miRNAs are involved in this process is still unknown. The purpose of this study is to explore whether IL-8 promotes cholesterol accumulation by enhancing miR-183 expression in macrophages and its underlying mechanism. METHODS AND RESULTS: Treatment of THP-1 macrophage-derived foam cells with IL-8 decreased ABCA1 expression and cholesterol efflux. Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-183 was highly conserved during evolution and directly inhibited ABCA1 protein and mRNA expression by targeting ABCA1 3'UTR. MiR-183 directly regulated endogenous ABCA1 expression levels. Furthermore, IL-8 enhanced the expression of miR-183 and decrease ABCA1 expression. Cholesterol transport assays confirmed that IL-8 dramatically inhibited apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux by increasing miR-183 expression. In contrast, treatment with anti-IL-8 antibody reversed these effects. CONCLUSION: IL-8 enhances the expression of miR-183, which then inhibits ABCA1 expression and cholesterol efflux. Our studies suggest that the IL-8-miR-183-ABCA1 axis may play an intermediary role in the development of atherosclerosis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Colesterol/metabolismo , Células Espumosas/metabolismo , Regulação da Expressão Gênica , Interleucina-8/metabolismo , MicroRNAs/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Espumosas/patologia , Humanos , Células THP-1
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