scholarly journals Celastrol Attenuates the Remodeling of Pulmonary Vascular and Right Ventricular in Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

2021 ◽  
Author(s):  
Huayang Li ◽  
Quan Liu ◽  
Yuan Yue ◽  
Shunjun Wang ◽  
Suiqing Huang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Vascular Remodeling ◽  
Protective Mechanism ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Rv Function

Abstract Background: Pulmonary arterial hypertension (PAH) is a progressive angio-proliferative disease associated with high morbidity and mortality rates. Although the histopathology of PAH is well described, its therapeutic option remains unsatisfactory. This study investigated the effect of celastrol treatment on PAH right ventricular (RV) dysfunction, RV remodeling and pulmonary vascular remodeling in rats as well as its possible mechanisms.Methods: PAH was induced in rats by a single subcutaneously injection of monocrotaline (MCT). After daily delivery of celastrol (1 mg/kg) or vehicle via intraperitoneal injection for 4 weeks, the effects of celastrol on RV function, fibrosis, and pulmonary vascular remodeling were assessed. The infiltration of macrophages, the expression of inflammatory cytokines, including MCP-1, IL-1β, IL-6, and IL-10, and the expression of NF-κB signaling pathway-associated proteins, IkBα, p-IKKα/β and p65 were further detected. Finally, the effect of celastrol on human pulmonary artery smooth cells (HPASMCs) proliferation under hypoxia was studied in vitro.Results: Rats with PAH had decreased RV function, increased RV fibrosis and pulmonary arteries with interstitial thickening and prominent media hypertrophy. Treatment with celastrol improved RV function, and attenuated RV fibrosis and pulmonary vascular remodeling. Significantly decreased macrophage infiltration, reduced levels of pro-inflammatory cytokines, increased level of anti-inflammatory cytokine and inhibited NF-κB signaling pathway were observed in the lung tissues of rats treated with celastrol. Moreover, celastrol significantly suppressed the proliferation of HPASMCs under hypoxia.Conclusions: We showed that in rats with PAH, celastrol could improve RV function, and attenuate RV and pulmonary vascular remodeling and HPASMCs proliferation under hypoxia. Suppression of the NF-κB signaling pathway may be a part of the protective mechanism.

scholarly journals Celastrol Attenuates the Remodeling of Pulmonary Vascular and Right Ventricular in Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

2021 ◽  
Author(s):  
huayang li ◽  
Quan Liu ◽  
Yuan Yue ◽  
Shunjun Wang ◽  
Suiqing Huang ◽  
...  
Keyword(s):  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Vascular Remodeling ◽  
Macrophage Infiltration ◽  
Protective Mechanism ◽  
High Morbidity ◽  
Pulmonary Vascular Remodeling ◽  
Rv Function

Abstract PurposePulmonary arterial hypertension (PAH) is a progressive angio-proliferative disease with high morbidity and mortality. Although the histopathology is well described, its therapeutic effect is still unsatisfactory. This study investigated the treatment of celastrol on PAH rats right ventricular (RV) dysfunction, RV remodeling and pulmonary vascular remodeling and its possible mechanisms.MethodsPAH in rats was induced by monocrotaline (MCT) single subcutaneously injection. After daily delivery of Celastrol (1mg/kg) or vehicle via intraperitoneal injection for 4 weeks, the effects of celastrol on RV function, fibrosis, and pulmonary vascular remodeling were assessed. Macrophage infiltration, expression of inflammatory cytokines, including MCP-1, IL-1β, IL-6, IL-10 and the expression of NF-kB signaling pathway-associated protein, IkBα, p-IKKα/β and p65 were further detected. Finally, the effect of celastrol on human pulmonary artery smooth cells (HPASMCs) proliferation under hypoxia was studied in vitro.ResultsRats with PAH had degressive RV function, increased RV fibrosis and pulmonary arteries with interstitial thickening and prominent media hypertrophy. Treatment with celastrol improved RV function, attenuated RV fibrosis and pulmonary vascular remodeling. Significantly deceased macrophage infiltration, lower level of pro-inflammatory cytokines, higher level of anti-inflammatory cytokine and inhibited NF-κB signaling pathway were observed in lung tissues of rats with celastrol treatment. Moreover, celastrol significantly suppressed the proliferation of HPASMCs under hypoxia. ConclusionsWe showed that, in rats with PAH, celastrol could improve RV function, attenuate RV and pulmonary vascular remodeling and the proliferation of HPASMCs under hypoxia. The suppression of NF-κB signaling pathway may be a part of the protective mechanism.

scholarly journals Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987859 ◽  
Author(s):  
Guosen Yan ◽  
Jinxia Wang ◽  
Tao Yi ◽  
Junfen Cheng ◽  
Haixu Guo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.

scholarly journals Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

2020 ◽  
Vol 318 (4) ◽  
pp. H853-H866 ◽  
Author(s):  
Yin Kang ◽  
Guangyan Zhang ◽  
Emma C. Huang ◽  
Jiapeng Huang ◽  
Jun Cai ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Lung Injury ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies. NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.

Abstract 12535: MicroRNA-663 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension by Targeting TGFβ1/smad2/3 Signaling

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ni Zhu ◽  
Pan Li ◽  
He Du ◽  
Yongwen Qin ◽  
Xianxian Zhao
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Tgf Β1

Objective: Pulmonary vascular remodeling due to excessive growth factor production and pulmonary artery smooth muscle cells (PASMCs) proliferation is the hallmark feature of pulmonary arterial hypertension (PAH). Recent studies suggest that miR-663 is a potent modulator for tumorigenesis and atherosclerosis. However, whether miR-663 involves in pulmonary vascular remodeling is still unclear. Methods and Results: By using quantitative RT-PCR, we found that miR-663 was highly expressed in normal human PASMCs. In contrast, circulating level of miR-663 dramatically reduced in PAH patients. In addition, in situ hybridization showed that expression of miR-663 was decreased in PAMSCs of PAH patients. Furthermore, MTT and cell scratch-wound assay showed that transfection of miR-663 mimics significantly inhibited platelet derived growth factor (PDGF)-induced PASMC proliferation and migration, while knockdown of miR-663 expression enhanced these effects. Mechanistically, dual-luciferase reporter assay revealed that miR-663 directly targets the 3’UTR of TGF-β1. Moreover, western blots and ELISA results showed that miR-663 decreased PDGF-induced TGF-β1 expression and secretion, which in turn suppressed the downstream smad2/3 phosphorylation and collagen I expression. Finally, intratracheal instillation of adeno-miR-663 dramatically attenuated pulmonary vascular remodeling and right ventricular hypertrophy, as well as right ventricular systolic pressure and mean pulmonary arterial pressure in MCT-induced PAH rat models. Conclusion: These results indicate that miR-663 is a potential biomarker for PAH. MiR-663 decreases PDGF-BB-induced PAMSCs proliferation and ameliorates pulmonary vascular remodeling and right ventricular hypertrophy in MCT-PAH by targeting TGF-β1/smad2/3 signaling. These findings suggest that miR-663 may represent as an attractive approach for the diagnosis and treatment of PAH.

scholarly journals Evaluation of right ventricular myocardial metabolism and pulmonary vascular remodeling in pulmonary arterial hypertension by positron emission tomography

2020 ◽  
Vol 26 (5) ◽  
pp. 501-508
Author(s):  
E. R. Molokova ◽  
D. V. Ryzhkova
Keyword(s):  
Positron Emission Tomography ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Emission Tomography ◽  
Clinical Prognosis ◽  
Pulmonary Vascular Remodeling ◽  
Positron Emission ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and severe form of pulmonary hypertension, which is characterized by pulmonary vascular remodeling, as well as metabolic and functional alterations in the right ventricular myocardium. The proven metabolic shift towards anaerobic glycolysis in the heart and lungs can be quantitatively and qualitatively evaluated with a molecular imaging technique — 2-[18F] fluoro-2-deoxy-Dglucose (FDG) positron emission tomography (PET). This review is devoted to the analysis of foreign scientific publications. There are presented research results that prove the diagnostic value of fused PET/computer tomography (CT) (PET/CT) images with FDG and other promising radiopharmaceuticals in patients with PAH. This tool allows estimation of the severity of the disease, to determine the clinical prognosis and monitor the effectiveness of treatment in each case. Furthermore, the methods of molecular visualization allow the analysis of the PAH pathogenesis and description of the new biologic targets, such as development factors of endothelial dysfunction and remodeling of pulmonary vasculature.

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