Special Issue on Mechanobiology and Diseases

Hanjoong Jo,신현정 대한의용생체공학회 2015 Biomedical Engineering Letters (BMEL) Vol.5 No.3

Regulation of Glucose Trnsport

Jo, Hanjoong,Hardy, Robert W .,McDonald, Jay M . 대한당뇨병학회 1991 Diabetes and Metabolism Journal Vol.15 No.1

Redox Going with Vascular Shear Stress

Noguchi, Noriko,Jo, Hanjoong Mary Ann Liebert 2011 ANTIOXIDANTS AND REDOX SIGNALING Vol.15 No.5

Novel Animal Models of Atherosclerosis

Amir Rezvan,Sanjoli Sur,Hanjoong Jo 대한의용생체공학회 2015 Biomedical Engineering Letters (BMEL) Vol.5 No.3

Atherosclerosis remains a significant cause of mortality andmorbidity in the world. It is now well established thatatherosclerosis is an inflammatory disease preferentiallyoccurring in curved or branched arterial regions, whereasstraight parts of the arteries are protected, suggesting a closerelationship between flow and atherosclerosis. Animalmodels of atherosclerosis are an important tool to understandthe pathophysiology of atherosclerosis and identify newtherapies. Various animal models have been used throughoutthe years, each contributing to scientific progress in the field,including different species such as pigeon, mice, rabbit,pig and nonhuman primates. In many cases, one or acombination of multiple interventions, including geneticmanipulation, hypercholesterolemia inducing diets, or surgicalinterventions are employed to induce atherosclerosis or toaccelerate or vary the severity and complexity of the lesions. In recent years, new animal models have been developed toaddress specific needs in the field of atherosclerosis research. Some of these models use surgical interventions to create adisturbed flow profile, and a few models have used largeranimals such as minipigs. While PCSK9 inhibition isbeing used as a new therapy for lowering cholesterol inhyperlipidemic patients, over-expression of PCSK9 hasrecently been exploited to induce atherosclerosis in animalmodels. No animal model can perfectly mimic the process inhuman disease, however each model may be successfullyused to elucidate a particular aspect of the pathophysiology. It is essential to understand the strengths and weaknesses ineach model in

Disturbed flow: p53 SUMOylation in the turnover of endothelial cells

Takabe, Wakako,Alberts-Grill, Noah,Jo, Hanjoong The Rockefeller University Press 2011 The Journal of cell biology Vol.193 No.5

<P>Disturbed blood flow induces apoptosis of vascular endothelial cells, which causes atherosclerosis. In this issue, Heo et al. (2011. <I>J. Cell Biol</I>. doi:10.1083/jcb.201010051) sheds light on p53’s role in this phenomenon. Disturbed flow induces peroxynitrite production, which activates protein kinase C ζ and it’s binding to the E3 SUMO (small ubiquitin-like modifier) ligase PIASy (protein inhibitor of activated STATy). This leads to p53 SUMOylation and its export to the cytosol, where it binds to the antiapoptotic protein Bcl-2 to induce apoptosis.</P>

Fibronectin-Dependent Cell Adhesion is Required for Shear-Dependent ERK Activation

Park, Heonyong,Shin, Jaeyoung,Lee, Jung Weon,Jo, Hanjoong The Korean Society for Integrative Biology 2004 Korean journal of biological sciences Vol.8 No.1

Endothellial cells are subjected to hemodynamic shear stress, the dragging force generated by blood flow. Shear stress regulates endothelial cell shape, structure, and function, including gene expression. Since endothelial cells must be anchored to their extracellular matrices(ECM) for their survival and growth, we hypothesized that ECMs are crucial for shear-dependent activation of extracellular signalactivated regulated kinase(ERK) that is important for cell proliferation. Shear stress-dependent activation of ERK was observed in cells plated on two different matrices, fibronectin and vitronectin(the two most physiologically relevant ECM in endothelial cells). We then treated bovine aortic endothelial cells(BAECs) with Arg-Gly-Asp(RGD) peptides that block the functional activation of integrin binding to fibronectin and vitronectin, and a nonfunctional peptide as a control. Treatment of cells with the RGD peptides, but not the control peptide, significantly inhibited ERK activity in a concentration-dependent manner. This supports the idea that integrin adhesion to the ligands, fibronectin and vitronectin, mediates shear stress-dependent activation of ERK. Subsequently, whereas antagonists of vitronectin(LM 609, an antibody for integrin ${\alpha}_{\gamma}$/${\beta}_3$ and XT 199, an antagonist specific for integrin ${\alpha}_{\gamma}$/${\beta}_3$) did not have any effect on shear-dependent activation of ERK, antagonists of fibronectin(a neutralizing antibody for integrin ${\alpha}_5$/${\beta}_1$or ${\alpha}_4$${\beta}_1$ and SM256) had an inhibitory effect. These results clearly demonstrate that mechanoactivation of ERK requires anchoring of endothelial cells to fibronectin through integrins.

Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells

Holliday, Casey J.,Ankeny, Randall F.,Jo, Hanjoong,Nerem, Robert M. American Physiological Society 2011 American journal of physiology, Heart and circulat Vol.301 No.3

<P> The role of endothelial cells (ECs) in aortic valve (AV) disease remains relatively unknown; however, disease preferentially occurs in the fibrosa. We hypothesized oscillatory shear (OS) present on the fibrosa stimulates ECs to modify mRNAs and microRNAs (miRNAs) inducing disease. Our goal was to identify mRNAs and miRNAs differentially regulated by OS and laminar shear (LS) in human AVECs (HAVECs) from the fibrosa (fHAVECs) and ventricularis (vHAVECs). HAVECs expressed EC markers as well as some smooth muscle cell markers and functionally aligned with the flow. HAVECs were exposed to OS and LS for 24 h, and total RNA was analyzed by mRNA and miRNA microarrays. We found over 700 and 300 mRNAs down- and upregulated, respectively, by OS; however, there was no side dependency. mRNA microarray results were validated for 26 of 28 tested genes. Ingenuity Pathway Analysis revealed thrombospondin 1 ( Thbs1) and NF-κB inhibitor-α ( Nfkbia) as highly connected, shear-sensitive genes. miRNA array analysis yielded 30 shear-sensitive miRNAs and 3 side-specific miRNAs. miRNA validation confirmed 4 of 17 shear-sensitive miRNAs and 1 of 3 side-dependent miRNAs. Using miRWalk and several filtering steps, we identified shear-sensitive mRNAs potentially targeted by shear-sensitive miRNAs. These genes and signaling pathways could act as therapeutic targets of AV disease. </P>

MicroRNA-663 upregulated by oscillatory shear stress plays a role in inflammatory response of endothelial cells

Ni, Chih-Wen,Qiu, Haiwei,Jo, Hanjoong American Physiological Society 2011 American journal of physiology, Heart and circulat Vol.300 No.5

<P> The mechanisms by which oscillatory shear stress (OS) induces, while high laminar shear stress (LS) prevents, atherosclerosis are still unclear. Here, we examined the hypothesis that OS induces inflammatory response, a critical atherogenic event, in endothelial cells by a microRNA (miRNA)-dependent mechanism. By miRNA microarray analysis using total RNA from human umbilical vein endothelial cells (HUVECs) that were exposed to OS or LS for 24 h, we identified 21 miRNAs that were differentially expressed. Of the 21 miRNAs, 13 were further examined by quantitative PCR, which validated the result for 10 miRNAs. Treatment of HUVECs with the miR-663 antagonist (miR-663-locked nucleic acids) blocked OS-induced monocyte adhesion, but not apoptosis. In contrast, overexpression of miR-663 increased monocyte adhesion in LS-exposed cells. Subsequent mRNA expression microarray study using HUVECs treated with miR-663-locked nucleic acids and OS revealed 32 up- and 3 downregulated genes, 6 of which are known to be involved in inflammatory response. In summary, we identified 10 OS-sensitive miRNAs, including miR-663, which plays a key role in OS-induced inflammatory responses by mediating the expression of inflammatory gene network in HUVECs. These OS-sensitive miRNAs may mediate atherosclerosis induced by disturbed flow. </P>

Fibronectin-Dependent Cell Adhesion is Required for Shear-Dependent ERK Activation

박헌용,Jaeyoung Shin,Jung Weon Lee,Hanjoong Jo 한국통합생물학회 2004 Animal cells and systems Vol.8 No.1

Endothelial cells are subjected to hemodynamic shear stress, the dragging force generated by blood flow. Shear stress regulates endothelial cell shape, structure, and function, including gene expression. Since endothelial cells must be anchored to their extracellular matrices (ECM) for their survival and growth, we hypothesized that ECMs are crucial for shear-dependent activation of extracellular signal-activated regulated kinase (ERK) that is important for cell proliferation. Shear stress-dependent activation of ERK was observed in cells plated on two different matrices, fibronectin and vitronectin (the two most physiologically relevant ECM in endothelial cells). We then treated bovine aortic endothelial cells (BAECs) with Arg-Gly-Asp (RGD) peptides that block the functional activation of integrin binding to fibronectin and vitronectin, and a nonfunctional peptide as a control. Treatment of cells with the RGD peptides, but not the control peptide, significantly inhibited ERK activity in a concentration-dependent manner. This supports the idea that integrin adhesion to the ligands, fibronectin and vitronectin, mediates shear stress-dependent activation of ERK. Subsequently, whereas antagonists of vitronectin (LM 609, an antibody for integrin avb3 and XT 199, an antagonist specific for integrin avb3) did not have any effect on shear-dependent activation of ERK, antagonists of fibronectin (a neutralizing antibody for integrin a5b1 or a4b1 and SM256) had an inhibitory effect. These results clearly demonstrate that mechanoactivation of ERK requires anchoring of endothelial cells to fibronectin through integrins.

Detection of low levels of nitric oxide using an electrochemical sensor.

Boo, Yong Chool,Mun, Gyeong In,Tressel, Sarah L,Jo, Hanjoong Humana Press 2011 Methods in molecular biology Vol.704 No.-

<P>Nitric oxide produced from nitric oxide synthases mediates various physiological and pathological events in biological systems. However, quantitative assessment of nitric oxide from biological sources remains a difficult task. Here we describe a procedure for the quantification of low levels of nitric oxide using a nitric oxide - selective electrochemical sensor. Nitric oxide is oxidized to nitrite and/or nitrate and accumulated in the aqueous media. First, nitrate in biological fluids or culture media is converted to nitrite by an enzymatic method. Nitrite is then chemically converted to equimolar NO in an acidic iodide bath, where nitric oxide is detected by the sensor. Using this method, the present study demonstrates siRNA -mediated suppression of nitric oxide synthase 3 leading to a significant decline of basal nitric oxide production in human umbilical vein endothelial cells. Basal nitric oxide production from HUVECs is also shown to be inhibited by N (G)-nitro-L: -arginine methyl ester but not by N (G)-nitro-D: -arginine methyl ester (D-NAME) D-NAME . The analytical method presented here provides a sensitive and convenient tool for measuring basal and stimulated nitric oxide production from biological sources.</P>