Browsing by Author "Shyy, John Y-J"

Now showing 1 - 6 of 6

Deep Sequencing and Bioinformatics Analysis of Endothelial MicroRNA under Hypoxia Stress
(2010-04-01)
Chen, Zhen
;
Sun, Wei
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Padmanabhan, Chellappan
;
Wang, Wei-Chi
;
Jin, Hailing
Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a
(2011-08-02)
Wu, Wei
;
Xiao, Han
;
Laguna-Fernandez, Andres
;
Villarreal, Guadalupe, Jr.
;
Wang, Kuei-Chun
Background-Upregulated by atheroprotective flow, the transcription factor Kruppel-like factor 2 (KLF2) is crucial for maintaining endothelial function. MicroRNAs (miRNAs) are noncoding small RNAs that regulate gene expression at the posttranscriptional level. We examined the role of miRNAs, particularly miR-92a, in the atheroprotective flow-regulated KLF2. Methods and Results-Dicer knockdown increased the level of KLF2 mRNA in human umbilical vein endothelial cells, suggesting that KLF2 is regulated by miRNA. In silico analysis predicted that miR-92a could bind to the 3' untranslated region of KLF2 mRNA. Overexpression of miR-92a decreased the expression of KLF2 and the KLF2-regulated endothelial nitric oxide synthase and thrombomodulin at mRNA and protein levels. A complementary finding is that miR-92a inhibitor increased the mRNA and protein expression of KLF2, endothelial nitric oxide synthase, and thrombomodulin. Subsequent studies revealed that atheroprotective laminar flow downregulated the level of miR-92a precursor to induce KLF2, and the level of this flow-induced KLF2 was reduced by miR-92a precursor. Furthermore, miR-92a level was lower in human umbilical vein endothelial cells exposed to the atheroprotective pulsatile shear flow than under atheroprone oscillatory shear flow. Anti-Ago1/2 immunoprecipitation coupled with real-time polymerase chain reaction revealed that pulsatile shear flow decreased the functional targeting of miR-92a precursor/KLF2 mRNA in human umbilical vein endothelial cells. Consistent with these findings, mouse carotid arteries receiving miR-92a precursor exhibited impaired vasodilatory response to flow. Conclusions-Atheroprotective flow patterns decrease the level of miR-92a, which in turn increases KLF2 expression to maintain endothelial homeostasis. (Circulation. 2011;124:633-641.)
MicroRNA-483 amelioration of experimental pulmonary hypertension
(2020-05-08)
Zhang, Jin
;
He, Yangyang
;
Yan, Xiaosong
;
Chen, Shanshan
;
He, Ming
Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA-seq and bioinformatics analyses showed that miR-483 targets several PAH-related genes, including transforming growth factor-beta (TGF-beta), TGF-beta receptor 2 (TGFBR2), beta-catenin, connective tissue growth factor (CTGF), interleukin-1 beta (IL-1 beta), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-beta, TGFBR2, beta-catenin, CTGF, IL-1 beta, and ET-1. In contrast, inhibition of miR-483 increased these genes in ECs. Rats with EC-specific miR-483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR-483. These results indicate that PAH is associated with a reduced level of miR-483 and that miR-483 might reduce experimental PH by inhibition of multiple adverse responses.
MicroRNA-483 amelioration of experimental pulmonary hypertension
(1970-01-01)
Zhang Jin
;
He Yangyang
;
Yan Xiaosong
;
Chen Shanshan
;
He Ming
Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA-seq and bioinformatics analyses showed that miR-483 targets several PAH-related genes, including transforming growth factor-beta (TGF-beta), TGF-beta receptor 2 (TGFBR2), beta-catenin, connective tissue growth factor (CTGF), interleukin-1 beta (IL-1 beta), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-beta, TGFBR2, beta-catenin, CTGF, IL-1 beta, and ET-1. In contrast, inhibition of miR-483 increased these genes in ECs. Rats with EC-specific miR-483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR-483. These results indicate that PAH is associated with a reduced level of miR-483 and that miR-483 might reduce experimental PH by inhibition of multiple adverse responses.
Oxidative Stress Activates Endothelial Innate Immunity via Sterol Regulatory Element Binding Protein 2 (SREBP2) Transactivation of MicroRNA-92a
(2015-03-03)
Chen, Zhen
;
Wen, Liang
;
Martin, Marcy
;
Hsu, Chien-Yi
;
Fang, Longhou
Background-Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. Methods and Results-Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Kruppel-like factor 2, and Kruppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1 beta. Conclusions-Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.
The C-Terminus of a Subunit Determines The Catalytic Activity of AMP-activated Protein Kinase
(2010-04-01)
Cui, Xiaopei
;
Gao, Haiqing
;
Hwang, Jenn-Kang
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Shyy, John Y-J
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生物資訊及系統生物研究所