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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.

2.
Hepatology ; 74(4): 2133-2153, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34133792

RESUMO

BACKGROUND AND AIMS: Hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, causes a large proportion of early graft failure and organ rejection cases. The identification of key regulators of hepatic I/R injury may provide potential strategies to clinically improve the prognosis of liver surgery. Here, we aimed to identify the role of tumor necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in hepatic I/R injury and further reveal its immanent mechanisms. APPROACH AND RESULTS: In the present study, we found that hepatocyte TNIP3 was markedly up-regulated in livers of both persons and mice subjected to I/R surgery. Hepatocyte-specific Tnip3 overexpression effectively attenuated I/R-induced liver necrosis and inflammation, but improved cell proliferation in mice, whereas TNIP3 ablation largely aggravated liver injury. This inhibitory effect of TNIP3 on hepatic I/R injury was found to be dependent on significant activation of the Hippo-YAP signaling pathway. Mechanistically, TNIP3 was found to directly interact with large tumor suppressor 2 (LATS2) and promote neuronal precursor cell-expressed developmentally down-regulated 4-mediated LATS2 ubiquitination, leading to decreased Yes-associated protein (YAP) phosphorylation at serine 112 and the activated transcription of factors downstream of YAP. Notably, adeno-associated virus delivered TNIP3 expression in the liver substantially blocked I/R injury in mice. CONCLUSIONS: TNIP3 is a regulator of hepatic I/R injury that alleviates cell death and inflammation by assisting ubiquitination and degradation of LATS2 and the resultant YAP activation.TNIP3 represents a promising therapeutic target for hepatic I/R injury to improve the prognosis of liver surgery.

4.
Hepatology ; 74(3): 1319-1338, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33894019

RESUMO

BACKGROUND AND AIMS: NAFLD has become the most common liver disease worldwide but lacks a well-established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms. METHODS AND RESULTS: In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 deficiency markedly deteriorates lipid accumulation in cultured hepatocytes and diet-induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase, the primary enzyme promoting cytosolic acetyl-coenzyme A production, and promotes its K48-linked ubiquitination-dependent degradation. Consistently, acetyl-coenzyme A was significantly accumulated in Sh3rf2-knockout hepatocytes and livers compared with wild-type controls, leading to enhanced de novo lipogenesis, cholesterol production, and resultant lipid deposition. CONCLUSION: SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and therefore represents a promising therapeutic target for related liver diseases.

5.
Epigenomics ; 12(24): 2189-2204, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33084403

RESUMO

Aim: To explore the potentially important role of miRNA 146b-5p (miR-146b) during the development of atherosclerosis. Materials & methods: Proliferation, migration and luciferase assays and mouse models were used to determine the functions of miR-146b. Results: miR-146b was identified as substantially upregulated in the aortic plaques of ApoE-/- mice as well as in response to inflammatory cytokines. Overexpression of miR-146b repressed proliferation and migration of vascular smooth muscle cells by downregulating Bag1 and Mmp16, respectively. Adeno-associated virus-mediated miR-146b overexpression inhibited neointima formation after carotid injury and suppressed atherosclerotic plaque formation in Western diet-induced ApoE-/- mice. Conclusion: miR-146b is a novel regulator of vascular smooth muscle cell function induced by inflammatory response, specifically in neointima formation, and offers a novel therapeutic strategy for treating atherosclerosis.

6.
Mol Metab ; 37: 100996, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32302712

RESUMO

OBJECTIVE: Long noncoding RNAs (lncRNAs) are currently considered to have a vital and wide range of biological functions, but the molecular mechanism underlying triglycerides metabolism remains poorly understood. This study aims to identify novel lncRNAs differentially expressed in rat livers with hypertriglyceridemia and elucidated the function role in TG metabolism. METHODS: Differentially expressions of lncRNAs in rat livers with hypertriglyceridemia were identified by transcriptome sequencing and validated by real-time PCR. The role of lnc19959.2 in triglyceride metabolism was assessed both in vitro and in vivo. RNA pulldown and RIP assays were conducted to evaluate the interactions between lnc19959.2 and its target proteins. ChIP and Dual report assays were performed to detect the interactions between transcription factors and promoters of its target genes. RESULTS: We identified a novel lncRNA, and lnc19959.2 was upregulated in rat livers with hypertriglyceridemia. The knockdown of lnc19959.2 has profound TG lowering effects in vitro and in vivo. Subsequently, the genome-wide analysis identified that the knockdown of lnc19959.2 caused the deregulation of many genes during TG homeostasis. Further mechanism studies revealed that lnc19959.2 upregulated ApoA4 expression via ubiquitinated transcription inhibitor factor Purb, while it specifically interacted with hnRNPA2B1 to downregulate the expression of Cpt1a, Tm7sf2, and Gpam, respectively. In the upstream pathway, palmitate acid upregulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) and facilitated its binding to the promoter of lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. CONCLUSIONS: Our findings provide novel insights into a new layer regulatory complexity of an lncRNA modulating triglyceride homeostasis by a novel lncRNA lnc19959.2.

7.
Mol Med Rep ; 19(5): 3459-3468, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864718

RESUMO

Abdominal aortic aneurysm (AAA) is an asymptomatic, potentially lethal disease whose ruptures have a high mortality rate. An effective pharmacological approach to decrease expansion or prevent the rupture of AAAs in humans remains lacking. Previous studies have suggested that activator protein 1 (c­Jun/AP­1) and C/EBP homologous protein (Chop) are involved in the development of AAA. The purpose of the present study was to investigate whether c­Jun/AP­1 mediates Chop overexpression in AAA. c­Jun/AP­1 and Chop protein levels were determined in an angiotensin II (Ang II)­induced AAA model using apolipoprotein E­deficient mice. Additionally, mouse aortic smooth muscle cells (MOVAS cell line) were treated with Ang II. Apoptosis was evaluated via TUNEL assay, MOVAS cell migration ability was assessed by monolayer wound healing assay and the levels of c­Jun/AP­1 and Chop were determined by western blotting, immunofluorescence and immunocytochemical assays. Following c­Jun silencing using c­Jun­specific small interfering (si)RNA, Chop expression was evaluated. Furthermore, chromatin immunoprecipitation (ChIP) was used to investigate whether c­Jun/Ap­1 binds directly to the DNA damage­inducible transcript 3 protein (Ddit3) promoter. It was observed that c­Jun/AP­1 and Chop were synchronously overexpressed in Ang II­induced AAA and Ang II­treated cells, and that apoptosis and migration were induced by Ang II. In addition, Chop was suppressed when c­Jun was silenced by targeted siRNA. Notably, the ChIP assay demonstrated that the DNA fragments pulled down by primary antibodies against c­Jun/Ap­1 were able to be amplified by (Ddit3) promoter­specific primers. c­Jun/AP­1 may therefore mediate Chop expression in MOVAS cells via Ddit3. These results suggested that c­Jun/AP­1 may be a novel target for AAA therapy.


Assuntos
Angiotensina II/efeitos adversos , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição CHOP/genética , Angiotensina II/metabolismo , Animais , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Modelos Animais de Doenças , Inativação Gênica , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Ligação Proteica , RNA Interferente Pequeno/genética , Fator de Transcrição CHOP/metabolismo
8.
Biosci Rep ; 39(4)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30850398

RESUMO

Hypoxia may cause abnormal proliferation and migration of the vascular smooth muscle cells (VSMCs) from the media to the intima. This contributes to vessel narrowing and accelerates the process of atherosclerosis. The association of the aberrant expression of long noncoding RNAs (lncRNAs) with the development and progression of atherosclerosis is well known; however, it is not well investigated in hypoxic VSMCs. Using a microarray approach, we identified 1056 and 2804 differentially expressed lncRNAs and mRNAs, respectively, in hypoxic and normoxic mouse aorta smooth muscle (MOVAS) cells. Of them, we randomly chose several lncRNAs and validated the microarray data using the quantitative PCR (qPCR) assay. Advanced bioinformatics analyses indicated that the up-regulated mRNAs were mainly involved in inflammatory responses, lipid metabolism, clearance of amyloid-ß peptide, citrate cycle (TCA cycle), TGF-ß signaling, and chemokine signaling. The down-regulated mRNAs were mainly involved in the apoptosis pathway, glycerolipid metabolism, Wnt signaling pathway, and MAPK signaling pathway. The constructed coexpression network indicated interactions between 87 lncRNAs and ten mRNAs. In addition, we demonstrated that the silence of lncRNA NONMMUT002434 expression could abrogate the migration and proliferation of smooth muscle cells dramatically. Our data provide comprehensive evidence on the differential expression of lncRNAs and mRNAs in hypoxic MOVAS cells, which may be valuable biomarkers for atherosclerotic diseases, and thereby facilitating diagnosis of atherosclerosis.


Assuntos
Aorta/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/biossíntese , RNA Mensageiro/biossíntese , Animais , Aorta/citologia , Hipóxia Celular , Linhagem Celular , Camundongos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia
9.
J Mol Cell Cardiol ; 123: 118-127, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30219518

RESUMO

BACKGROUND: Myocardial infarction (MI) contributes to the development of cardiac remodeling and heart failure. Insufficient post-MI myocardial angiogenesis has been identified as a non-negligible event which precipitates heart failure progression. Previous studies reported that cytochrome P450 epoxygenase and its metabolites exerted beneficial effects on cardiovascular diseases. However, the role of cytochrome P450 2J2 (CYP2J2) in post-MI heart failure is incompletely understood. METHODS AND RESULTS: First, western blot and real-time PCR analyses showed that CYP2J2 expression increased clearly in patients with acute MI and old MI, compared to control. Second, echocardiography and histological studies showed that transgenic (TG) rats had relatively preserved cardiac function, as well as attenuated remodeling, and reduced scar formation, compared to the wild-type (WT) littermates after MI eight weeks. Importantly, the cardioprotective effect induced by CYP2J2 overexpression was abrogated by VEGFR2 inhibitor-cediranib. More intriguingly, positron emission computed Tomography (PET) analyses showed that TG rats displayed better myocardial perfusion than WT rats. We found that these effects were linked to increasing circulating EETs and enhancing myocardial angiogenesis. Additionally, in vitro study demonstrated that 11, 12-epoxyeicosatrienoic acid (11, 12-EET) induced more robust tube formation and markedly increased VEGF-A and bFGF expression in hypoxia and normoxia. Finally, western blot analyses uncovered that CYP2J2 and 11, 12-EET promoted angiogenesis via the Jagged1/Notch1 signaling pathway. CONCLUSIONS: Our findings demonstrate that CYP2J2 improves cardiac function by increasing the concentration of circulating EETs, and boosting angiogenesis via the Jagged1/Notch1 signaling pathway in MI-induced heart failure.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Endotélio/metabolismo , Expressão Gênica , Proteína Jagged-1/metabolismo , Miocárdio/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Testes de Função Cardíaca , Hemodinâmica , Humanos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Neovascularização Patológica/metabolismo , Especificidade de Órgãos/genética , Ratos
10.
Oncotarget ; 8(38): 63073-63083, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28968972

RESUMO

Acute myocarditis is an uncommon and potentially life-threatening disease. Scoring systems are essential for predicting outcome and evaluating the therapy effect of adult patients with acute myocarditis. The aim of this study was to determine the value of the Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation IV (APACHE IV) and second Simplified Acute Physiology Score (SAPS II) scoring systems in predicting short-term mortality of these patients. We retrospectively analyzed data from 305 adult patients suffering from acute myocarditis between April 2005 and August 2016. The association between the value of admission SOFA, APACHE IV and SAPS II scores and risk of short-term mortality was determined. Multivariate Cox analysis showed that SOFA, APACHE IV and SAPS II scores were independent risk factors of death in patients with acute myocarditis. For each scoring system, Kaplan-Meier analysis showed that the cumulative short-term mortality was significantly higher in patients with higher admission scores compared with those with lower admission scores. For the prediction of short-term mortality in a patient with acute myocarditis, SAPS II had the highest accuracy followed by the APACHE IV and SOFA scores.

11.
PLoS One ; 12(4): e0174821, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28369137

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially lethal disease with extremely poor survival rates once the aneurysm ruptures. Statins may exert beneficial effects on the progression of AAA. However, the underlying mechanism is still not known. The purpose of the present study is to investigate whether statin could inhibit AAA formation by inhibiting the endoplasmic reticulum (ER) stress signal pathway. METHODS: A clinically relevant AAA model was induced in Apolipoprotein E-deficient (ApoE-/-) mice, which were infused with angiotensin II (Ang II) for 28 days. These mice were randomly divided into following 4 groups: saline infusion alone; Ang II infusion alone; Ang II infusion plus Atorvastatin (20mg/kg/d); and Ang II infusion plus Atorvastatin (30mg/kg/d). Besides, another AAA model was induced in C57 mice with extraluminal CaCl2, which were divided into 3 groups: sham group, CaCl2-induced AAA group, and CaCl2-induced AAA plus atorvastatin (20mg/kg/d) group. Then, aortic tissue was excised for further examinations, respectively. In vitro studies, Ang II with or without simvastatin treatment were applied to the vascular smooth muscle cells (VSMCS) and Raw 264.7 cells. The ER stress signal pathway, apoptosis and inflammatory response were evaluated by in vivo and in vitro assays. RESULTS: We found that higher dose of atorvastatin can effectively suppress the development and progression of AAA induced by Ang II or CaCl2. Mechanistically, the activation of ER stress and inflammatory response were found involved in Ang II-induced AAA formation. The atorvastatin infusion significantly reduced ER stress signaling proteins, the number of apoptotic cells, and the activation of Caspase12 and Bax in the Ang II-induced ApoE-/- mice, compared with mice treated by Ang II alone. Furthermore, proinflammatory cytokines such as IL-6, IL-8, IL-1ß were all remarkably inhibited after atorvastatin treatment. In vitro, the inhibitory effect of simvastatin on the ER stress signal pathway could be observed in both vascular smooth muscle cells and macrophages, and these inhibitory effects of statin were in a dose-dependent manner. In addition, apoptosis was induced with Ang II treatment. The maximal inhibitory effect of simvastatin on apoptosis was observed at 10 µmol/l. CONCLUSIONS: We conclude that higher dose of statin can effectively suppress the development of AAA, and reduce ER stress, ER stress-associated apoptosis signaling pathways, and inflammatory response. These findings reveal a new mechanism underlying the inhibitory effect of statin on AAA formation/progression.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Atorvastatina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Angiotensina II , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cloreto de Cálcio , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Distribuição Aleatória
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