Caveolin-1 Regulates Rac1 Activation and Rat Pulmonary Microvascular Endothelial Hyperpermeability Induced by TNF-α

Shao, Min; Yang, Yue; Sun, Guan; You, Qinghai; Wang, Nan; Zhang, Dan

doi:10.1371/journal.pone.0055213

Cited by 15 publications

(13 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cav-1 associates with the hypervariable C-terminal domain of Rac1 through its scaffolding domain [24]. Cav-1 depletion led to the activation of Rac1 and consequently induced a Rac1 phenotype, increased cell spreading and loss of polarity [25][26][27]. In this present study, Cav-1 depletion increased Rac1 activity despite miR-199a-5p knockdown.…”

Section: Discussionsupporting

confidence: 58%

MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome

Zeng

Chen

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Pulmonary microvascular endothelial cell (PMVEC) proliferation and angiogenesis contribute to the development of hepatopulmonary syndrome (HPS). MicroRNA-199a-5p (miR-199a-5p) has emerged as a potent regulator of angiogenesis, and its expression levels significantly decrease in the serum of patients with hepatopathy. However, it has not been reported about whether miR-199a-5p might control PMVEC proliferation. Here, we described the miR-199a-5p governing PMVEC proliferation in HPS. Methods: PMVECs were treated with rat serum from common bile duct ligation (CBDL) or sham. MiR-199a-5p mimic or inhibitor was used to change the miR-199a-5p expression. Knockdown of caveolin-1 (Cav-1) was performed using siRNA. NSC-23766 was used to inhibit Rac1 activity. Gene and protein expressions were quantified by qRT-PCR and western blot. Cell proliferation was analyzed by ³H-TdR incorporation and CCK-8 assays. Stress fibers were detected by immunofluorescence. Results: CBDL rat serum induced the down-regulation of miR-199a-5p. Delivery of miR-199a-5p suppressed the CBDL rat serum-induced PMVEC proliferation whereas knockdown of miR-199a-5p promoted PMVEC proliferation. This was accompanied by a decrease and an increase in Cav-1 expression, respectively. Cav-1 siRNA abolished the enhancement of PMVEC proliferation induced by the miR-199a-5p inhibition. Although stress fibers were disrupted in Cav-1 deficient cells, NSC-23766 increased stress fibers and contributed to cell proliferation. Conclusions: CBDL rat serum induced down-regulation of miR-199a-5p in PMVECs, which led to an increase of Cav-1 gene expression. Increased Cav-1 expression, by inhibiting Rac1 activity, led to the formation of stress fibers, which contribute to PMVEC proliferation and thus the pathogenesis of HPS.

show abstract

Section: Discussionsupporting

confidence: 58%

MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome

Zeng

Chen

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Several studies in endothelial cells in culture have shown that TNF-α increases monolayer permeability within 1h to 5h [52,53,54,55,56], although sometimes permeability is studied for up to 24h [57] at which time the mechanisms leading to increased permeability may differ [58]. In the first hours, TNF-α causes MLC- and Rho-kinase-dependent actin stress fiber formation [51] in cultured endothelial cells.…”

Section: Platelet-activating Factor (Paf)mentioning

confidence: 99%

“…This response is mediated by Rho-kinase which has consequently been linked to the ensuing increase in permeability [54,59], although this mechanism was questioned in one study [52]. Besides Rho-kinase, the following signaling molecules have been implicated in the TNF-α induced permeability increase in vitro : P-Rex1/Rac1 [55,56], PKCα [60], p38 [54,61], NO derived from endothelial NOS [58,62] leading to formation of peroxynitrite [63], and tyrosine kinase-mediated phosphorylation of VE-cadherin [55,64]. Interestingly, despite the fact that monolayer permeability usually starts to increase earliest 1h after stimulation with TNF-α, many of the signalling events that have been linked to the increase in permeability reach their maximum within 5-20 minutes, such as the activation of RhoA [59], rac1 [55], MAP kinases [54], src kinase [64], the phosphorylation of VE-cadherin [55], and the inactivation of myosin phosphatase target subunit 1 [59].…”

Section: Platelet-activating Factor (Paf)mentioning

confidence: 99%

Differential Regulation of Lung Endothelial Permeability in Vitro and in Situ

Uhlig

Yang

Waade

et al. 2014

Cell Physiol Biochem

View full text Add to dashboard Cite

In the lungs, increased vascular permeability can lead to acute lung injury. Because vascular permeability is regulated primarily by endothelial cells, many researchers have studied endothelial cell monolayers in culture, in order to understand the pathomechanisms of pulmonary edema. Such studies are based on the assumption that endothelial cells in culture behave like endothelial cells in situ. Here we show that this assumption is largely unfounded. Cultured endothelial cells show profound differences compared to their physiological counterparts, including a dysregulated calcium homeostasis. They fail to reproduce the pulmonary responses to agents such as platelet-activating factor. In contrast, they respond in a Rho-kinase depend fashion to thrombin, LPS or TNF. This is a striking finding for three reasons: (i) in the lungs, none of these agents increases vascular permeability by a direct interaction with endothelial cells; (ii) The endothelial Rho-kinase pathway seems to play little role in the development of pulmonary edema; (iii) This response pattern is similar for many endothelial cells in culture irrespective of their origin, which is in contrast to the stark heterogeneity of endothelial cells in situ. It appears that most endothelial in culture tend to develop a similar phenotyp that is not representative of any of the known endothelial cells of the lungs. We conclude that at present cultured endothelial cells are not useful to study the pathomechanisms of pulmonary edema.

show abstract

“…Furthermore, a previous study demonstrated that treatment with NSC-23766, which disturbs the Rac1-specific GEFs T-cell lymphoma invasion and metastasis 1 and Trio, also decreased TER and promoted intercellular gap formation (19). Our previous study also demonstrated that TNF-α-induced PMVECs barrier breakdown was, at least in part, mediated by Rac1 inactivation (20). In addition, as the majority of findings on the microvascular endothelium are in accordance with existing reports that macrovascular endothelial cells are negatively affected by constitutively inactive Rac1 mutants (9,18), it is well-established that Rac1 appears to improve endothelial barrier properties under resting conditions.…”

Section: Discussionmentioning

confidence: 78%

Rac1 mediates HMGB1-induced hyperpermeability in pulmonary microvascular endothelial cells via MAPK signal transduction

Shao

Tang

et al. 2015

Molecular Medicine Reports

Self Cite

View full text Add to dashboard Cite

The pathology of acute respiratory distress syndrome (ARDS) is closely associated with the failure of alveolar‑capillary barrier integrity and alveolar filling by high protein pulmonary edema, resulting from hyperpermeability. High mobility group box 1 (HMGB1) is a novel late mediator of sepsis, which is specifically involved in endotoxin‑induced acute lung injury and sepsis‑associated lethality. Although the role of HMGB1 in endothelial cell cytoskeletal rearrangement and vascular permeability have been investigated preliminarily, the molecular mechanisms remain to be fully elucidated. As the ras‑related C3 botulinum toxin substrate 1 (Rac1) gene is important role in regulating microvascular barrier maintenance, the present study was designed to determine whether Rac1 is involved in HMGB1‑induced hyperpermeability in pulmonary microvascular endothelial cells (PMVECs). The results of the present study demonstrated that HMGB1 induced dose and time‑dependent decreases in transendothelial electrical resistance (TER). Notably, HMGB1 induced a dose‑dependent increase in the activity and expression levels of Rac1. Using small interfering RNA and an agonist of Rac1, the present study demonstrated that Rac1 was a novel factor mediating the HMGB1‑induced decrease in TER via extracellular signal‑regulated kinase and p38 mitogen‑activated protein kinase (MAPK) activation. These data suggested that Rac1 is involved in HMGB1‑induced hyperpermeability in PMVECs via MAPK signal transduction.

show abstract

Caveolin-1 Regulates Rac1 Activation and Rat Pulmonary Microvascular Endothelial Hyperpermeability Induced by TNF-α

Cited by 15 publications

References 60 publications

MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome

MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome

Differential Regulation of Lung Endothelial Permeability <b><i>in Vitro</i></b> and <b><i>in Situ</i></b>

Rac1 mediates HMGB1-induced hyperpermeability in pulmonary microvascular endothelial cells via MAPK signal transduction

Contact Info

Product

Resources

About