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강덕희,강신욱,정현주,김유선,양철우,Richard J. Johnson 연세대학교의과대학 2004 Yonsei medical journal Vol.45 No.6
Maintenance of healthy endothelium is essential to vascular homeostasis, and preservation of endothelial cell function is critical for transplant allograft function. Damage of microvascular endothelial cells is now regarded as a characteristic feature of acute vascular rejection and chronic allograft nephropathy, which is an important predictor of graft loss and is often associated with transplant vasculopathy. In this review, we will discuss the role of microvascular endothelium, in renal allograft dysfunction, particularly as it relates to markers of endothelial dysfunction and endothelial repair mechanisms. We also discuss the potential for therapies targeting endothelial dysfunction and transplant graft vasculopathy.
Song, Young Hun,Estrada, Daniel A.,Johnson, Richard S.,Kim, Somi K.,Lee, Sang Yeol,MacCoss, Michael J.,Imaizumi, Takato National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.49
<P><B>Significance</B></P><P>In many plants, seasonal flowering is a crucial aspect of maximizing reproductive fitness. Changes in day length (or photoperiod) provide the most reliable cue that enables plants to anticipate approaching seasonal variation in the surrounding environment. The induction of the <I>FLOWERING LOCUS T</I> (<I>FT</I>) gene controlled by the light-stabilized CONSTANS (CO) protein is the key mechanism for photoperiodic flowering in <I>Arabidopsis thaliana</I>. The CO/FT module is highly conserved in many plant species, including major crops. In <I>Arabidopsis</I>, blue-light–signaling pathways are essential for the stabilization of CO protein. Here we show a unique role of GIGANTEA in photoperiodic flowering through the interactions with two homologous proteins, FLAVIN-BINDING, KELCH REPEAT, F-BOX1 and ZEITLUPE, which antagonistically control CO stability.</P><P>Many plants measure changes in day length to synchronize their flowering time with appropriate seasons for maximum reproductive success. In <I>Arabidopsis</I>, the day-length–dependent regulation of CONSTANS (CO) protein stability is crucial to induce <I>FLOWERING LOCUS T</I> (<I>FT</I>) expression for flowering in long days. The FLAVIN-BINDING, KELCH REPEAT, F-BOX1 (FKF1) protein binds to CO protein specifically in the long-day afternoon and stabilizes it, although the mechanism remains unknown. Here we demonstrated that the FKF1-interacting proteins GIGANTEA (GI) and ZEITLUPE (ZTL) are involved in CO stability regulation. First, our immunoprecipitation-mass spectrometry analysis of FKF1 revealed that FKF1 forms an S-phase kinase-associated protein 1 (Skp1)/Cullin(CUL)/F-box complex through interactions with <I>Arabidopsis</I> Skp1-like 1 (ASK1), ASK2, and CUL1 proteins and mainly interacts with GI protein in vivo. GI interacts with CO directly and indirectly through FKF1. Unexpectedly, the <I>gi</I> mutation increases the CO protein levels in the morning in long days. This <I>gi</I>-dependent destabilization of CO protein was cancelled by the <I>fkf1</I> mutation. These results suggest that there are other factors likely influenced by both <I>gi</I> and <I>fkf1</I> mutations that also control CO stability. We found that ZTL, which interacts with GI and FKF1, may be one such factor. ZTL also interacts with CO in vivo. The CO protein profile in the <I>ztl</I> mutant resembles that in the <I>gi</I> mutant, indicating that ZTL activity also may be changed in the <I>gi</I> mutant. Our findings suggest the presence of balanced regulation among FKF1, GI, and ZTL on CO stability regulation for the precise control of flowering time.</P>
Yu, Min-A,Sá,nchez-Lozada, Laura G,Johnson, Richard J,Kang, Duk-Hee Lippincott Williams Wilkins, Inc. 2010 Journal of Hypertension Vol.28 No.6
AIMS: Oxidative stress is known to be a major mechanism of endothelial dysfunction, which plays a key role in the development of cardiovascular disease. Although uric acid is one of the most important antioxidants, recent studies have suggested that uric acid may have a causal role in endothelial dysfunction. In order to understand the paradoxical association of uric acid with oxidative stress and vascular disease, we investigated whether uric acid induced oxidative stress in human vascular endothelial cells. We also examined whether uric acid-induced changes in redox status were related to aging and death of endothelial cells or an activation of local renin–angiotensin system, another mediator of endothelial dysfunction. METHODS: Endothelial senescence and apoptosis were evaluated by senescence-associated &bgr;-galactosidase staining and annexin V–propidium iodide staining in primary isolated human umbilical vein endothelial cells (HUVECs). Production of reactive oxygen species was assessed by dichlorofluorescein diacetate staining. mRNA expression of angiotensinogen, angiotensin-converting enzyme and the receptors of angiotensin II was evaluated by real-time PCR, and angiotensin II levels were measured in uric acid-stimulated HUVECs. RESULTS: Uric acid-induced senescence and apoptosis in HUVECs at concentrations more than 6 and 9 mg/dl, respectively. Uric acid-induced alterations in cell proliferation, senescence and apoptosis were blocked by probenecid, enalaprilat or telmisartan. Uric acid significantly increased production of reactive oxygen species beginning at 5 min, and uric acid-induced senescence and apoptosis of HUVECs were ameliorated by N-acetylcysteine or tempol. Uric acid also upregulated the expression of angiotensinogen, angiotensin-converting enzyme and angiotensin II receptors and increased angiotensin II levels, which was ameliorated with tempol. CONCLUSION: Uric acid-induced aging and death of human endothelial cells are medicated by local activation of oxidative stress and the renin–angiotensin system, which provides a novel mechanism of uric acid-induced endothelial dysfunction. Therapies targeting uric acid may be beneficial in cardiovascular disease.
Kang, Duk-Hee,Park, Sung-Kwang,Lee, In-Kyu,Johnson, Richard J. American Society of Nephrology 2005 Journal of the American Society of Nephrology Vol.16 No.12
<P>Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal-regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by 3H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.</P>