Asymmetric dimethylarginine induces apoptosis via p38 MAPK/caspase-3-dependent signaling pathway in endothelial cells

Jiang, De-Jian; Jia, Sujie; Dai, Zhong; Li, Yuan‐Jian

doi:10.1016/j.yjmcc.2006.01.021

Cited by 93 publications

(61 citation statements)

References 27 publications

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“…31 It has also reported that p38 MAPK is activated by ADMA in HUVECs. 32 In the present study, we have observed that ADMA-induced upregulation of ACE is suppressed in HCAECs transfected with DDAH2 ( Figure 8A). Furthermore, ADMA stimulates p38 MAP kinase and ACE protein expression, both of which are blocked by a specific p38MAP kinase inhibitor (SB203580), but not by a p44/42 MAP kinase inhibitor (PD98059; Figure 8B, 8C).…”

Section: Discussionsupporting

confidence: 60%

Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2

Hara

Wakino

Tatematsu

et al. 2007

Circulation Research

114

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Abstract-Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investigate the in vivo role of DDAH2, we generated trangenic mice overexpressing DDAH2. The transgenic mice manifested reductions in plasma ADMA and elevations in cardiac NO levels but no changes in systemic blood pressure (SBP), compared with the wild-type mice. When infused into wild-type mice for 4 weeks, ADMA elevated SBP and caused marked medial thickening and perivascular fibrosis in coronary microvessels, which were accompanied by ACE protein upregulation and cardiac oxidative stress. The treatment with amlodipine reduced SBP but failed to ameliorate the ADMA-induced histological changes. In contrast, these changes were abolished in transgenic mice, with a reduction in plasma ADMA. In coronary artery endothelial cells, ADMA activated p38 MAP kinase and the ADMA-induced ACE upregulation was suppressed by p38 MAP kinase inhibition by SB203580. In wild-type mice, long-term treatment with angiotensin II increased plasma ADMA and cardiac oxidative stress and caused similar vascular injury. In transgenic mice, these changes were attenuated. The present study suggests that DDAH2/ADMA regulates cardiac NO levels but has modest effect on SBP in normal conditions. Under the circumstances where plasma ADMA are elevated, including angiotensin II-activated conditions, ADMA serves to contribute to the development of vascular injury and increased cardiac oxidative stress, and the overexpression of DDAH2 attenuates these abnormalities. Collectively, the DDAH2/ADMA pathway can be a novel therapeutic target for vasculopathy in the ADMA or angiotensin II-induced pathophysiological conditions. (Circ Res. 2007;101:e2-e10.)Key Words: DDAH2 Ⅲ ADMA Ⅲ angiotensin II A symmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS). Substantial evidence has been accumulated that plasma ADMA mediates the endothelial dysfunction and serves as a marker of risk for cardiovascular disease. 1-3 ADMA is degraded by the enzyme, dimethylarginine dimethylaminohydrolase (DDAH), and would subsequently affect NO metabolism. It has been demonstrated that DDAH is composed of 2 isoforms, DDAH1 and DDAH2, 4 each of which stems from different chromosomes and differs in several aspects. DDAH1 and 2 appear to have distinct tissue distributions, with DDAH1 predominating in the tissues that express nNOS and DDAH2 being coexpressed with eNOS in highly vascularized tissues. 5 Moreover, in cultured human endothelial cells, DDAH1 is uniformly distributed in the cytosol and nucleus, whereas DDAH2 is found only in the cytosol. 6 The different characteristics between these 2 isoforms suggest different physiological functions.Physiological function of DDAH1 has been elucidated by the studies using transgenic (TG) mice overexpressing DDAH1 7 and DDAH1 knockout (KO) mice. 8 In TG mice, tissue DDAH1 expression is increased and t...

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Section: Discussionsupporting

confidence: 60%

Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2

Hara

Wakino

Tatematsu

et al. 2007

Circulation Research

114

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“…30 Interestingly, ADMA enhances phosphorylation of p38 MAPK in endothelial cells. 31 In our present study, exposure to ADMA led to degranulation of PMNs; therefore, ADMA acted as a mediator of the activation state of PMNs (ie, enhanced MPO activity, superoxide release). Another possible mechanism by which altered NO bioavailability may influence PMN degranulation has been described by Fortenberry et al 32 These investigators showed that NO impairs oxidative cell function of PMNs and increases neutrophil cell death in part by enhancing DNA fragmentation, resulting in a markedly impaired release of toxic granula content (ie, MPO).…”

Section: Discussionsupporting

confidence: 50%

Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase

et al. 2011

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Background-The nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) and the leukocyte-derived hemoprotein myeloperoxidase (MPO) are associated with cardiovascular diseases. Activation of monocytes and polymorphonuclear neutrophils (PMNs) with concomitant release of MPO is regulated in a nitric oxide-dependent fashion. The aim of the study was to investigate a potential 2-way interaction between ADMA and MPO. Methods and Results-Ex vivo, ADMA uptake by isolated human PMNs, the principal source of MPO in humans, significantly impaired nitric oxide synthase activity determined by gas chromatography-mass spectrometry. In humans, short-term ADMA infusion (0.0125 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) significantly increased MPO plasma concentrations. Functionally, PMN exposure to ADMA enhanced leukocyte adhesion to endothelial cells, augmented NADPH oxidase activity, and stimulated PMN degranulation, resulting in release of MPO. In vivo, a 28-day ADMA infusion (250 mol ⅐ kg Ϫ1 ⅐ d Ϫ1 ) in C57Bl/6 mice significantly increased plasma MPO concentrations, whereas this ADMA effect on MPO was attenuated by human dimethylarginine dimethylaminohydrolase1 (hDDAH1) overexpression. Moreover, the MPO-derived reactive molecule hypochlorous acid impaired recombinant hDDAH1 activity in vitro. In MPO Ϫ/Ϫ mice, the lipopolysaccharide-induced increase in systemic ADMA concentrations was abrogated. Conclusions-ADMA profoundly impairs nitric oxide synthesis of PMNs, resulting in increased PMN adhesion to endothelial cells, superoxide generation, and release of MPO. In addition, MPO impairs DDAH1 activity. Our data reveal an ADMA-induced cycle of PMN activation, enhanced MPO release, and subsequent impairment of DDAH1 activity. These findings not only highlight so far unrecognized cytokine-like properties of ADMA but also identify MPO as a regulatory switch for ADMA bioavailability under inflammatory conditions. (Circulation. 2011;124:2735-2745.)

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“…Secondly, P38 MAPK activation leads to caldesmon phosphorylation and dissociation of caldesmon-myosin complex, leading to actin cytoskeleton rearrangement and stress fiber formation [6]. Jiang et al [4] did some research on ADMA-induced HUVEC apoptosis, and found which was achieved via p38 MAPK/caspase-3-dependent signaling pathway in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that ADMA could activate p38MAPK/Caspase-3 pathway [4], and activated p38MAPK would trigger the formation of stress fibers [5,6]. Stress fibers are composed of Factin, a kind of cytoskeleton protein.…”

mentioning

confidence: 99%

Original article. The role of p38MAPK in asymmetric dimethylarginineinduced cytoskeleton and cellular permeability changes in cultured endothelial cells

Zhou

Zhang

et al. 2011

Asian Biomedicine

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Background: Asymmetric dimethylarginine (ADMA) induces endothelial cell barrier dysfunction via cytoskeleton activation and contraction. It is supposed that activated p38 mitogen-activated protein kinase (MAPK) would trigger the formation of stress fibers and increase cellular permeability. Objective: Explore p38 MAPK as a potentially important enzyme in ADMA-mediated endothelial cell contractile response and permeability change. Methods: Human umbilical endothelial cells (HUVECs) were cultured, where ADMA and/or SB203580 (the specific inhibitor of p38MAPK) were used to stimulate HUVECs. Immunofluorescent staining was carried out to examine the expression and distribution of F-actin, flow cytometry was used to quantify F-actin, and Transwell was applied to test cellular permeability with FITC-labelled human serum albumin (HSA). Scanning electronic microscopy (SEM) was utilized to observe the changes of intercellar contact. Results: ADMA induced significant p38MAPK activation in a dose-dependent manner, which correlated with increased stress fibers. SB-203580 attenuated the formation of actin stress fiber and the increase of cellular permeability induced ADMA in the HUVECs (p<0.01, LSCM; p<0.01, cytometry; p<0.05, Transwell). Widened intercellular space induced by ADMA was detected and could be inhibited by SB-203580 (SEM). SB-203580 alone had no effect on cytoskeleton and cellular permeability. Conclusion: p38MAPK activation participated in cytoskeleton and cellular permeability changes induced by ADMA in HUVECs.

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Asymmetric dimethylarginine induces apoptosis via p38 MAPK/caspase-3-dependent signaling pathway in endothelial cells

Cited by 93 publications

References 27 publications

Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2

Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2

Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase

Original article. The role of p38MAPK in asymmetric dimethylarginineinduced cytoskeleton and cellular permeability changes in cultured endothelial cells

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