Aspirin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing the ERK/MAPK pathway

Gao, Hua; Cheng, Yuqing; Zong, Liguo; Huang, Lingxia; Qiao, Chenchen; Li, Wei; Gong, Beilei; Hu, Jian; Liu, Haitao; Wang, Xiaojing; Zhao, Chengling

doi:10.1080/10641963.2016.1210620

Cited by 27 publications

(22 citation statements)

References 34 publications

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“…The role of inflammation is increasingly being recognized in the pathogenesis of PAH [ 34 ]. Recent studies have described inflammation as a characteristic feature of many forms of PAH in both humans and animals [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB is recognized as a transcription factor that mediates the expression of TNF-α, particularly in endothelial vascular cells. TNF-α is a proinflammatory cytokine with potent modulatory effects on pulmonary circulation [ 34 ]. Some researchers have reported that the TNF-α-mediated inhibition of the metabolic enzyme pyruvate dehydrogenase contributes to the pathogenesis of PAH, and elevated serum TNF-α levels are observed in patients with pulmonary hypertension secondary to chronic thromboembolic disease and connective tissue disease [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

et al. 2018

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Background: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. Several studies have demonstrated that betaine possesses outstanding anti-inflammatory effects. However, whether betaine exerts protective effects on PAH by inhibiting inflammatory responses in the lungs needs to be explored. To test our hypothesis, we aimed to investigate the effects of betaine on monocrotaline-induced PAH in rats and attempted to further clarify the possible mechanisms. Methods: PAH was induced by monocrotaline (50 mg/kg) and oral administration of betaine (100, 200, and 400 mg/kg/day). The mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricle hypertrophy index were used to evaluate the development of PAH. Hematoxylin and eosin staining and Masson staining were performed to measure the extents of vascular remodeling and proliferation in fibrous tissue. Monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were also detected by immunohistochemical staining. Nuclear factor-κB (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were assessed by Western blot. Results: This study showed that betaine improved the abnormalities in right ventricular systolic pressure, mean pulmonary arterial pressure, right ventricle hypertrophy index, and pulmonary arterial remodeling induced by monocrotaline compared with the PAH group. The levels of MCP-1 and ET-1 also decreased. Western blot indicated that the protein expression levels of NF-κB, TNF-α, and IL-1β significantly decreased (p < 0.01). Conclusion: Our study demonstrated that betaine attenuated PAH through its anti-inflammatory effects. Hence, the present data may offer novel targets and promising pharmacological perspectives for treating monocrotaline-induced PAH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

et al. 2018

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“…In dexamethasone-induced thymocyte cells apoptosis, ERK1/2 is suppressed, which causes calcium ion pool to dysfunction and prevents the phosphorylation of bcl-2, thereby accelerating the apoptotic process [ 45 , 46 ]. Moreover, ERK/MAPK had been demonstrated to be involved in MCT-induced PAH and aspirin treatment attenuates PAH by suppressing ERK1/2 signaling pathway in rats [ 47 ]. Our present study showed that in MCT-induced PAH the expression of p-ERK/ERK and apoptosis-resistant associated proteins such as bcl-2, bcl-xl were up-regulated, but pro-apoptosis protein caspase-3 was inhibited.…”

Section: Discussionmentioning

confidence: 99%

PCPA protects against monocrotaline-induced pulmonary arterial remodeling in rats: potential roles of connective tissue growth factor

Bai

Zhao

et al. 2017

Oncotarget

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The purpose of this study was to investigate the mechanism of monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and determine whether 4-chloro-DL-phenylalanine (PCPA) could inhibit pulmonary arterial remodeling associated with connective tissue growth factor (CTGF) expression and downstream signal pathway. MCT was administered to forty Sprague Dawley rats to establish the PAH model. PCPA was administered at doses of 50 and 100 mg/kg once daily for 3 weeks via intraperitoneal injection. On day 22, the pulmonary arterial pressure (PAP), right ventricle hypertrophy index (RVI) and pulmonary artery morphology were assessed and the serotonin receptor-1B (SR-1B), CTGF, p-ERK/ERK were measured by western blot or immunohistochemistry. The concentration of serotonin in plasma was checked by ELISA. Apoptosis and apoptosis-related indexes were detected by TUNEL and western blot. In the MCT-induced PAH models, the PAP, RVI, pulmonary vascular remodeling, SR-1B index, CTGF index, anti-apoptotic factors bcl-xl and bcl-2, serotonin concentration in plasma were all increased and the pro-apoptotic factor caspase-3 was reduced. PCPA significantly ameliorated pulmonary arterial remodeling induced by MCT, and this action was associated with accelerated apoptosis and down-regulation of CTGF, SR-1B and p-ERK/ERK. The present study suggests that PCPA protects against the pathogenesis of PAH by suppressing remodeling and inducing apoptosis, which are likely associated with CTGF and downstream ERK signaling pathway in rats.

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“…While no studies have evaluated whether platelets within the lungs of patients who died or received a lung transplant for PH were activated, pulmonary artery thromboses are increased in patients with PH and anti‐platelet therapies targeting the platelet hemostatic response demonstrate clear benefit in patients with chronic thromboembolic PH (Chaouat, Weitzenblum, & Higenbottam, 1996; Moser & Bloor, 1993; Wagenvoort, 1980). Antibody‐induced thrombocytopenia and treatment with pharmacologic platelet inhibitors (aspirin and dipyridamole) protect rats from monocrotaline and hypoxia‐induced PH (Gao et al, 2017; Keith, Will, Huxtable, & Weir, 1987; Mlczoch, Tucker, Weir, Reeves, & Grover, 1978; Shen, Shen, Pu, & He, 2011). Additionally, mice with a platelet‐specific deletion of toll‐like receptor 4 are protected from hypoxia‐induced PH (Bauer et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Platelet activation in experimental murine neonatal pulmonary hypertension

et al. 2020

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Serotonin (5‐HT) contributes to the pathogenesis of experimental neonatal pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD). Platelets are the primary source of circulating 5‐HT and is released upon platelet activation. Platelet transfusions are associated with neonatal mortality and increased rates of BPD. As BPD is often complicated by PH, we tested the hypothesis that circulating platelets are activated and also increased in the lungs of neonatal mice with bleomycin‐induced PH associated with BPD. Newborn wild‐type mice received intraperitoneal bleomycin (3 units/kg) three times weekly for 3 weeks. Platelets from mice with experimental PH exhibited increased adhesion to collagen under flow (at 300 s−1 and 1,500 s−1) and increased expression of the αIIbβ3 integrin and phosphatidylserine, markers of platelet activation. Platelet‐derived factors 5‐HT and platelet factor 4 were increased in plasma from mice with experimental PH. Pharmacologic blockade of the 5‐HT 2A receptor (5‐HT 2A R) prevents bleomycin‐induced PH and pulmonary vascular remodeling. Here, platelets from mice with bleomycin‐induced PH demonstrate increased 5‐HT 2A R expression providing further evidence of both platelet activation and increased 5‐HT signaling in this model. In addition, bleomycin treatment increased lung platelet accumulation. In summary, platelets are activated, granule factors are released, and are increased in numbers in the lungs of mice with experimental neonatal PH. These results suggest platelet activation and release of platelet‐derived factors may increase vascular tone, promote aberrant angiogenesis, and contribute to the development of neonatal PH.

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Aspirin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing the ERK/MAPK pathway

Cited by 27 publications

References 34 publications

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

PCPA protects against monocrotaline-induced pulmonary arterial remodeling in rats: potential roles of connective tissue growth factor

Platelet activation in experimental murine neonatal pulmonary hypertension

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