Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition

Chen, Weiguo; Pendyala, Srikanth; Natarajan, Viswanathan; Garcia, Joe G.N.; Jacobson, Jeffrey R.

doi:10.1152/ajplung.00428.2007

Cited by 89 publications

(99 citation statements)

References 45 publications

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“…Circulating blood cells from septic patients generate higher levels of phorbol ester-stimulated O 2 À production compared with those in control subjects, and this activation is inhibited by simvastatin, a widely used cholesterolreducing drug (28). Further, recent data indicate that simvastatin markedly decreases LPS-induced O 2 À production in human pulmonary artery ECs via dual inhibitory effects on RhoA and Rac1 (17). Together, these studies suggest that excessive generation of ROS by activation of phagocytic and nonphagocytic NOX enzymes may induce endothelial damage or activation with the subsequent loss of barrier function and pulmonary edema or both, key features of ALI=ARDS.…”

Section: Nox Enzymes In Acute Lung Injurymentioning

confidence: 79%

NOX Enzymes and Pulmonary Disease

Griffith

Pendyala²,

Hecker³

et al. 2009

Antioxidants & Redox Signaling

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The primary function of the lung is to facilitate the transfer of molecular oxygen (O 2 ; dioxygen) from the atmosphere to the systemic circulation. In addition to its essential role in aerobic metabolism, O 2 serves as the physiologic terminal acceptor of electron transfer catalyzed by the NADPH oxidase (NOX) family of oxidoreductases. The evolution of the lungs and circulatory systems in vertebrates was accompanied by increasing diversification of NOX family enzymes, suggesting adaptive roles for NOX-derived reactive oxygen species in normal physiology. However, this adaptation may paradoxically carry detrimental consequences in the setting of overwhelming=persistent environmental stressors, both infectious and noninfectious, and during the process of aging. Here, we review current understanding of NOX enzymes in normal lung physiology and their pathophysiologic roles in a number of pulmonary diseases, including lung infections, acute lung injury, pulmonary arterial hypertension, obstructive lung disorders, fibrotic lung disease, and lung cancer. Antioxid. Redox Signal. 11, 2505-2516.

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Section: Nox Enzymes In Acute Lung Injurymentioning

confidence: 79%

NOX Enzymes and Pulmonary Disease

Griffith

Pendyala²,

Hecker³

et al. 2009

Antioxidants & Redox Signaling

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130

112

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“…These activities of statins may be associated with Rho/Rho kinase signaling Statins can inhibit the prenylation of Ras and Rho leading to inactivation of Rhp/Rho kinase which then delays the development of atherosclerosis (Chiba et al, 2008;Chen et al, 2008 Abbreviations: Flu, Fluvastatin; TNF-, tumor necrosis factor-; TF, tissue factor; HUVECs, human umbilical vein endothelial cells; ELISA, enzyme-linked immunosorbent assay; RT-PCR, real time polymerase chain reaction; mRNA, messenger ribonucleic acid; MVA, mevalonic acid; cDNA, complementary deoxyribonucleic acid; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; PVDF, polyvinylidene fluoride; TBST, TRIS-Buffered Saline Tween-20; DMEM, Dulbecco's modified eagle's medium.…”

Section: Discussionmentioning

confidence: 99%

Department of Tea Science, Zhejiang University, Hangzhou 310058, P. R. China.

Jiang¹,

Kang²,

Yuan³

et al. 2011

Afr. J. Pharm. Pharmacol.

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To investigate the regulatory role of RhoA/Rho kinase in the effects of fluvastatin (Flu) on the tumor necrosis factor-(TNF-) induced expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) which may provide basis for the prevention of arterial thrombosis, HUVECs in logarithmic phase were divided into TNF-group, Flu group and TNF-+Flu group. enzyme-linked immunosorbent assay (ELISA), real time polymerase chain reaction (RT-PCR) and western blot assay were employed to detect the content of TF, messenger ribonucleic acid (mRNA) expression of TF and protein expressions of TF and activated RhoA, respectively. Then, angiotensin II (Ang II) and Y27632 were used to treat these cells which were then divided into control group, TNF+Ang II group, AngII group, TNF-group and TNF-+Y27632 group. Western blot assay was performed to detect the protein expression of TF. After TNF-treatment, the content and mRNA and protein expressions of TF were markedly increased when compared with the control group (P<0.05). However, the content and mRNA and protein expressions of TF in Flu group were significantly lower than those in TNF-group (P<0.05). Our results showed TNF-could induce TF expression in HUVECs and activate RhoA, which, however, were inhibited by Flu. Ang II treatment could increase the TNF-induced TF expression in HUVECs which however was inhibited Y27632. Flu could effectively inhibit the TNF-induced protein and mRNA expressions of TF in HUVECs in which RhoA/Rho signaling pathway may play an important role.

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“…Using pharmacologic inhibitors that target ROCK, previous studies have demonstrated an important role for ROCK in regulating endothelial cell (EC) actin cytoskeleton organization and permeability increases during an inflammatory response in vivo and in vitro, especially during the early and acute phase of the inflammatory responses (13,14). All these inhibitors similarly inhibit ROCK1 and ROCK2.…”

Section: R Ho Kinase (Rock)mentioning

confidence: 99%

Activation of Rho Kinase Isoforms in Lung Endothelial Cells during Inflammation

Mong

Wang

2009

The Journal of Immunology

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Rho kinase (ROCK) is a downstream effector of Rho family GTPases, and two highly homologous isoforms, ROCK1 and ROCK2, are similarly inhibited by the widely used pharmacologic inhibitors. In endothelial cells (ECs), activation of ROCK regulates myosin L chain (MLC) phosphorylation, stress fiber formation and permeability increases during inflammation. This study examined isoform-specific ROCK activation in lung ECs in vitro using human pulmonary microvascular ECs and ex vivo using freshly isolated lung ECs from mice. In unstimulated human as well as mouse lung ECs, ROCK2 activity was greater than ROCK1 activity. TNF-α stimulation induced activation of both ROCK1 and ROCK2 in cultured human ECs. Studies using lung ECs freshly isolated from mice showed that intratracheal instillation of LPS induced ROCK activation in lung ECs that was inhibited by treating animals with fasudil, a pharmacologic ROCK inhibitor, and that both ROCK1 and ROCK2 were activated. Small interference RNA targeting ROCK1 or ROCK2 was used to examine their functions in regulating MLC phosphorylation and permeability increases induced by TNF-α in human ECs. TNF-α-induced MLC phosphorylation required ROCK activation. Inhibition of ROCK1 alone was not sufficient to prevent TNF-α-induced MLC phosphorylation, whereas inhibition of ROCK2 prevented TNF-α-induced late MLC phosphorylation at 24 h. Although ROCK1 was dispensable for TNF-α-induced MLC phosphorylation, ROCK1 was required for TNF-α-induced early permeability increases. Therefore, ROCK1 and ROCK2 are both activated by TNF-α and can be functionally separated in the signaling pathways leading to TNF-α-induced MLC phosphorylation and permeability increases.

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Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition

Cited by 89 publications

References 45 publications

NOX Enzymes and Pulmonary Disease

NOX Enzymes and Pulmonary Disease

Department of Tea Science, Zhejiang University, Hangzhou 310058, P. R. China.

Activation of Rho Kinase Isoforms in Lung Endothelial Cells during Inflammation

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