Effects of monocrotaline pyrrole and thrombin on pulmonary endothelial cell junction and matrix adhesion proteins

Taylor, D. W.; Lamé, Michael W.; Nakayama, Lynn S; Segall, H. J.; Wilson, Dennis W

doi:10.1016/s0300-483x(02)00582-6

Cited by 5 publications

(5 citation statements)

References 36 publications

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“…Because proper assembly and oligomerization of Cav-1 in the Golgi requires its lipid modification on three specific Cys residues, without which this plasma membrane scaffolding protein remains trapped in the Golgi (57), we suggest that covalent modification of Cys residues on target proteins, including Cav-1, may initiate the trafficking block in the Golgi. In addition, MCTP has been reported to derivatize the cytoskeletal protein actin covalently (61,68). However, we did not observe altered microtubule or actin organization per se in cells treated with MCTP.…”

Section: Discussioncontrasting

confidence: 77%

“…Although the MCT-induced PH model has been extensively studied during the past four decades, the cellular mechanisms contributing to megalocytosis of PAECs are only now beginning to be explored (for reviews, see 22,28,43,61,67). This laboratory (28) proposed recently that MCT induced a disruption of caveolin (Cav)-1/raft function in PAEC, resulting in widespread alterations in cell signaling, including stimulation of promitogenic STAT3 and ERK1/2 signaling.…”

mentioning

confidence: 98%

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Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism

Shah

Patel

Sehgal

2005

American Journal of Physiology-Cell Physiology

100

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Pyrrolizidine alkaloids initiate disease in the lung (pulmonary hypertension), liver (veno-occlusive disease and cirrhosis), and kidneys (afferent arteriolar block and mesangiolysis) by inducing a megalocytotic phenotype in target endothelial and parenchymal cells. A "hit-and-run" type of exposure to the bioactive pyrrolizidine results, within 2-3 days, in enlarged cells with large nuclei and enlarged Golgi and endoplasmic reticulum, while the cells remain in G2/M block. In the present study, we recapitulated monocrotaline pyrrole (MCTP)-induced megalocytosis in cultures of bovine pulmonary arterial endothelial cells (PAEC), human Hep3B hepatocytes, human type II-like alveolar epithelial cells (A549), and human pulmonary arterial smooth muscle cells (PASMC) and investigated the subcellular mechanism involved. There was an inverse relationship between reduction in caveolin (Cav)-1 levels and stimulation of promitogenic STAT3 and ERK1/2 cell signaling. In megalocytotic PAEC, the Golgi scaffolding protein GM130 was shifted from membranes with heavy density to those with a lighter density. This lighter Golgi fraction was enriched for hypo-oligomeric Cav-1, indicating dysfunctional trafficking of cargo. Immunofluorescence imaging studies confirmed the trapping of Cav-1 in a GM130-positive Golgi compartment. There was an increase in Ser25 phosphorylation of GM130 (typically a prelude to Golgi fragmentation and mitosis) and increased association between pGM130, cdc2 kinase, and Cav-1. Nevertheless, megalocytotic MCTP-treated cells showed reduced entry into mitosis upon stimulation with 2-methoxyestradiol (2-ME), reduced 2-ME-induced Golgi fragmentation, and a slowing of Golgi reassembly after nocodazole-induced fragmentation. These data suggest that a disruption of the trafficking and mitosis sensor functions of the Golgi may represent the subcellular mechanism leading to MCTP-induced megalocytosis ("the Golgi blockade hypothesis").

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Section: Discussioncontrasting

confidence: 77%

mentioning

confidence: 98%

Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism

Shah

Patel

Sehgal

2005

American Journal of Physiology-Cell Physiology

100

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“…Monocrotaline (MCT) is an 11‐membered macrocyclic diester member of the pyrrolizidine alkaloid family of plant toxins that produces a delayed onset yet progressive pulmonary vascular disease resulting in pulmonary hypertension in SD rats [10]. Pulmonary vascular changes begin with an early mild subintimal edema in capillaries of the interalveolar septa and walls of alveolar ducts.…”

Section: Discussionmentioning

confidence: 99%

The Extracellular Signal‐Regulated Kinase Is Involved in the Effects of Sildenafil on Pulmonary Vascular Remodeling

Zeng

Jiang

et al. 2010

Cardiovascular Therapeutics

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Pulmonary hypertension is a group of diseases comprising vascular constriction and obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, for example, sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats. We investigate the mechanisms of sildenafil on the pulmonary vascular remodeling of pulmonary hypertension induced by monocrotaline (MCT) in rats. Thirty Sprague-Dawley rats (weighing 200-220 g) were administered with MCT abdominal cavity injection or equivalent volume of normal saline (NS) (which were treated as C group n = 10) to induce pulmonary hypertension model. Fourteen days later, 20 MCT treated rats were randomly fed with sildenafil (25mg/kg/day) or placebo as S, P group (10 rats for each group), respectively. Another 6 weeks later, mean pulmonary artery pressure (mPAP), index of right ventricular hypertrophy (RV/LV+S) of all animals were measured under general anesthesia. Pulmonary tissue was collected to investigate pathological features of pulmonary arteries and to measure protein expression of ERK 1 /ERK 2 and MKP1. After 6 weeks, there were significant elevated mPAP and RV/LV+S in both P and S groups. The ratio of wall thickness to vessel diameter in pulmonary arteries with diameters <200 μm were increased in both P and S groups. But the ratio of wall thickness to vessel diameter was smaller in S group than that in P group. The phosphorylation level of ERK 1 /ERK 2 were elevated in both P and S groups, but the level of phosphorlation ERK 1 /ERK 2 were lower in S group than that in P group. Intriguingly, the expression level of MKP1 was significantly increased in both S and P groups, while it was higher in S group than that in P group. The Sildenafil can decrease mPAP and inhibit the progress of pulmonary vascular remodeling in pulmonary hypertension rats. The ERK-MAP kinase signaling pathway might play a role during this process.

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“…One aspect of endothelium dysfunction contributing to PAH is the continuous damage of PAECs, resulting in increased vessel permeability 24 . We therefore injected EB dye via tail vein to assess the endothelium integrity in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…One aspect of endothelium dysfunction contributing to PAH is the continuous damage of PAECs, resulting in increased vessel permeability. 24 We therefore injected EB dye via tail vein to assess the endothelium integrity in vivo. Though no vessel leakage manifested in both unstimulated WT and Cirp-KO rats (Figure 4B), elevated extravasation of EB dye into lungs was detected following MCT injection with Cirp-KO rats presenting much higher permeability two weeks after MCT treatment (Figure 4B).…”

Section: Cirp Regulated Mctp-induced Rpaecs Apoptosis and Permeabilit...mentioning

confidence: 99%

Deficiency of cold‐inducible RNA‐binding protein exacerbated monocrotaline‐induced pulmonary artery hypertension through Caveolin1 and CAVIN1

Liu

Wang

et al. 2021

J Cellular Molecular Medi

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Cold‐inducible RNA‐binding protein (CIRP) was a crucial regulator in multiple diseases. However, its role in pulmonary artery hypertension (PAH) is still unknown. Here, we first established monocrotaline (MCT)‐induced rat PAH model and discovered that CIRP was down‐regulated predominantly in the endothelium of pulmonary artery after MCT injection. We then generated Cirp‐knockout (Cirp‐KO) rats, which manifested severer PAH with exacerbated endothelium damage in response to MCT. Subsequently, Caveolin1 (Cav1) and Cavin1 were identified as downstream targets of CIRP in MCT‐induced PAH, and the decreased expression of these two genes aggravated the injury and apoptosis of pulmonary artery endothelium. Moreover, CIRP deficiency intensified monocrotaline pyrrole (MCTP)‐induced rat pulmonary artery endothelial cells (rPAECs) injuries both in vivo and in vitro, which was counteracted by Cav1 or Cavin1 overexpression. In addition, CIRP regulated the proliferative effect of conditioned media from MCTP‐treated rPAECs on rat pulmonary artery smooth muscle cells, which partially explained the exceedingly thickened pulmonary artery intimal media in Cirp‐KO rats after MCT treatment. These results demonstrated that CIRP acts as a critical protective factor in MCT‐induced rat PAH by directly regulating CAV1 and CAVIN1 expression, which may facilitate the development of new therapeutic targets for the intervention of PAH.

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Effects of monocrotaline pyrrole and thrombin on pulmonary endothelial cell junction and matrix adhesion proteins

Cited by 5 publications

References 36 publications

Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism

Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism

The Extracellular Signal‐Regulated Kinase Is Involved in the Effects of Sildenafil on Pulmonary Vascular Remodeling

Deficiency of cold‐inducible RNA‐binding protein exacerbated monocrotaline‐induced pulmonary artery hypertension through Caveolin1 and CAVIN1

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