Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension

Li, Xiaohui; Peng, Jun; Tan, Na; Wu, Weihua; Li, Tingting; Shi, Ruizheng; Li, Yuan‐Jian

doi:10.1016/j.vph.2010.09.002

Cited by 30 publications

(27 citation statements)

References 34 publications

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“…The signaling pathways involved in monocrotaline‐induced endothelial injury and pulmonary hypertension that are well known and well studied include Smad, TGF‐β/Alk5, and Rho . These pathways also appear to be or associated with the downstream events on activation of CaSR, providing an additional line of support for the role of CaSR in mediating the effect of monocrotaline.…”

Section: Discussionmentioning

confidence: 98%

Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Xiao

Tian

et al. 2017

JAHA

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BackgroundMonocrotaline has been widely used to establish an animal model of pulmonary hypertension. The molecular target underlying monocrotaline‐induced pulmonary artery endothelial injury and pulmonary hypertension remains unknown. The extracellular calcium–sensing receptor (CaSR) and particularly its extracellular domain hold the potential structural basis for monocrotaline to bind. This study aimed to reveal whether monocrotaline induces pulmonary hypertension by targeting the CaSR.Methods and ResultsNuclear magnetic resonance screening through WaterLOGSY (water ligand‐observed gradient spectroscopy) and saturation transfer difference on protein preparation demonstrated the binding of monocrotaline to the CaSR. Immunocytochemical staining showed colocalization of monocrotaline with the CaSR in cultured pulmonary artery endothelial cells. Cellular thermal shift assay further verified the binding of monocrotaline to the CaSR in pulmonary arteries from monocrotaline‐injected rats. Monocrotaline enhanced the assembly of CaSR, triggered the mobilization of calcium signaling, and damaged pulmonary artery endothelial cells in a CaSR‐dependent manner. Finally, monocrotaline‐induced pulmonary hypertension in rats was significantly attenuated or abolished by the inhibitor, the general or lung knockdown or knockout of CaSR.ConclusionsMonocrotaline aggregates on and activates the CaSR of pulmonary artery endothelial cells to trigger endothelial damage and, ultimately, induces pulmonary hypertension.

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Section: Discussionmentioning

confidence: 98%

Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Xiao

Tian

et al. 2017

JAHA

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“…On one hand, elevated levels of ADMA were shown to be positively associated with reduced bioavailability of NO in different in vivo and in vitro models of PH [13][14][15][16][17]. On the other hand, it was discovered that ADMA significantly enhanced the production of ROS, proliferation of human and rat pulmonary smooth muscle cells [29,54] and bovine pulmonary artery endothelial cells [21].…”

Section: Discussionmentioning

confidence: 99%

“…ADMA was shown to increase the superoxide and ROS production by inducing the uncoupling of eNOS (described as a loss of eNOS dimer) [22,26,58,59]. Additionally ADMA induced formation of stress fibers and focal adhesions, blocked cell motility, and increased the permeability in porcine and rat pulmonary endothelial cells [18,24,54]. Third, the potential mechanisms of ADMA action in pulmonary endothelial cells were linked to (i) increased activity of Rho GTPases, which were shown to be important in regulation of endothelial barrier function [24] and (ii) decreased protein kinase G-mediated phosphorylation of vasodilator-stimulated phosphoprotein and Rac1, responsible for remodeling of the actin cytoskeleton and intracellular junctions [18].…”

Section: Discussionmentioning

confidence: 99%

Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha

Pekarová

Koudelka

Kolářová

et al. 2015

Vascular Pharmacology

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“…11 Briefly, the PA’s were opened and the luminal surface scraped into porcine EC growth media (Cell Applications, San Diego, CA). SMCs from the PA’s were cultured using the outgrowth technique 12 . The PA’s were minced into 2mm × 2mm pieces and cultured in Smooth Muscle Growth Media 2; (Promocell, Heidelberg, Germany) containing 20% FBS (Life Technologies, Grand Island, NY).…”

Section: Methodsmentioning

confidence: 99%

Pulmonary Artery Endothelial Cell Phenotypic Alterations in a Large Animal Model of Pulmonary Arteriovenous Malformations After the Glenn Shunt

Kavarana

Mukherjee

Eckhouse

et al. 2013

The Annals of Thoracic Surgery

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Background: Longevity of the superior cavopulmonary connection (SCPC) is limited by the development of pulmonary arteriovenous malformations (PAVM). The goal of this study was to determine whether phenotypic changes in pulmonary artery endothelial cells (PAEC) that favor angiogenesis occur with PAVM formation. Methods: A superior vena cava to right pulmonary artery connection was constructed in 5 pigs. Pulmonary arteries were harvested at 6-8 weeks following surgery to establish cultures of PAEC and smooth muscle cells, to determine cell proliferation, gene expression, and tubule formation. Abundance of proteins related to angiogenesis was measured in lung tissue. Results: Contrast echocardiography revealed right-to-left shunting, consistent with PAVM formation. While the proliferation of smooth muscle cells from the right pulmonary artery (RPA) (shunted side) and left pulmonary artery (LPA) (non- shunted side) were similar, right PAEC proliferation was significantly higher. Expression profiles of genes encoding cellular signaling proteins were higher in PAECs from the RPA vs. LPA. Protein abundance of angiopoietin-1, and Tie-2 (angiopoietin receptor) were increased in the right lung (both p<0.05). Tubule formation was increased in endothelial cells from the RPA compared to the LPA (404±16 vs. 199±71 tubules/mm2, respectively p<0.05). Conclusions: These findings demonstrate that PAVMs developed in a clinically relevant animal model of SCPC. This study found that PAVM development occurred concomitantly with differential changes in PAEC proliferative ability and phenotype. Moreover, there was a significant increase in the angiopoietin/Tie-2 complex in the right lung, which may provide novel therapeutic targets to attenuate PAVM formation following a SCPC.

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Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension

Cited by 30 publications

References 34 publications

Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha

Pulmonary Artery Endothelial Cell Phenotypic Alterations in a Large Animal Model of Pulmonary Arteriovenous Malformations After the Glenn Shunt

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