Inhibition of Src activation reverses pulmonary vascular remodeling in experimental pulmonary arterial hypertension via Akt/mTOR/HIF-1 signaling pathway

2019 ◽  
Vol 380 (1) ◽  
pp. 36-46 ◽  
Author(s):  
Pengfei Liu ◽  
Yue Gu ◽  
Jie Luo ◽  
Peng Ye ◽  
Yaguo Zheng ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Signaling Pathway ◽  
Vascular Remodeling ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Src Activation

scholarly journals The protective effects of MSC-EXO against pulmonary arterial hypertension through inhibition of Wnt/BMP signaling pathway

2020 ◽  
Author(s):  
Zhaohua Zhang ◽  
Xiaoli Liu ◽  
LiLi Ge ◽  
Shanshan Zhang ◽  
Jue Wang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Signaling Pathway ◽  
Vascular Remodeling ◽  
Smooth Muscle Actin ◽  
Bmp Signaling ◽  
Human Umbilical Cord ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Abstract Background The aim of the study was to explore the mechanism of mesenchymal human umbilical cord msenchymal stem cells derived exosomes (MSC-EXO) against experimental pulmonary artery hypertension (PAH) pulmonary vascular remodeling . Methods and results After PAH model was successful established, the animals received tail vein injections of MSC-EXO. Post-operation, the pulmonary artery pressure was measured, and the lung tissues were stained to evaluate the pulmonary vascular remodeling. Our results showed that MSC-EXO could significantly inhibit the pulmonary arterial hypertension, attenuate pulmonary vascular remodeling and lung fibrosis in vivo . Furthermore, the hypoxia-induced pulmonary artery endothelial cell (PAEC) model was used in vitro . Our results showed the expression of CD31, V-Ecadherin, Wnt5a, Wnt11, BMPR2 and Smad1/5/8 were significantly higher, but the expression of alpha smooth muscle actin (a-SMA), β-catenin, cyclin D1 and Smad2/3 were significantly lower in in MSC-EXO administration group then that in MCT or hypoxia group. Moreover, the present study found that BMP signaling suppressed obviously when the cells were transfection with Wnt5a siRNA. Conclusion In conclusion, these results suggested that MSC-EXO could protect PAH vascular remodeling through regulation of Wnt/BMP signaling pathway.

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 Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 795
Author(s):  
Maria Callejo ◽  
Daniel Morales-Cano ◽  
Gema Mondejar-Parreño ◽  
Bianca Barreira ◽  
Sergio Esquivel-Ruiz ◽  
...  
Keyword(s):  
Vitamin D ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Function ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Standard Diet ◽  
Pulmonary Vascular Remodeling ◽  
Vitamin D Levels ◽  
Pulmonary Arterial ◽  
K Currents

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.

ID: 123: ROLE OF MICRORNA-1 IN REGULATING PULMONARY VASCULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION

2016 ◽  
Vol 64 (4) ◽  
pp. 969.1-969 ◽  
Author(s):  
JR Sysol ◽  
J Chen ◽  
S Singla ◽  
V Natarajan ◽  
RF Machado ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

RationalePulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by increased pulmonary arterial pressure and resistance due in part to uncontrolled vascular remodeling. The mechanisms contributing to vascular remodeling in PAH are poorly understood and involve rampant pulmonary artery smooth muscle cell (PASMC) proliferation. We recently demonstrated the important role of sphingosine kinase 1 (SphK1), a lipid kinase producing pro-proliferative sphingosine-1-phosphate (S1P), in the development of pulmonary vascular remodeling in PAH. However, the regulatory processes involved in upregulation of SphK1 in this disease are unknown.ObjectiveIn this study, we aimed to identify novel molecular mechanisms governing the regulation of SphK1 expression, with a focus on microRNA (miR). Using both in vitro studies in pulmonary artery smooth muscle cells (PASMCs) and an in vivo mouse model of experimental hypoxia-mediated pulmonary hypertension (HPH), we explored the role of miR in controlling SphK1 expression in the development of pulmonary vascular remodeling.Methods and ResultsIn silico analysis identified hsa-miR-1-3p (miR-1) as a candidate targeting SphK1. We demonstrate miR-1 is down-regulated by hypoxia in human PASMCs and in lung tissues of mice with HPH, coinciding with upregulation of SphK1 expression. PASMCs isolated from patients with PAH had significantly reduced expression of miR-1. Transfection of human PASMCs with miR-1 mimics significantly attenuated activity of a SphK1-3'-UTR luciferase reporter construct and SphK1 protein expression. miR-1 overexpression in human PASMCs also inhibited proliferation and migration under normoxic and hypoxic conditions, both important in pathogenic vascular remodeling in PAH. Finally, we demonstrated that intravenous administration of miR-1 mimics prevents the development of experimental HPH in mice and attenuates induction of SphK1 in PASMCs.ConclusionThese data demonstrate that miR-1 expression in reduced in PASMCs from PAH patients, is modulated by hypoxia, and regulates the expression of SphK1. Key phenotypic aspects of vascular remodeling are influenced by miR-1 and its overexpression can prevent the development of HPH in mice. These studies further our understanding of the mechanisms underlying pathogenic pulmonary vascular remodeling in PAH and could lead to novel therapeutic targets.Supported by grants NIH/NHLBI R01 HL127342 and R01 HL111656 to RFM, NIH/NHLBI P01 HL98050 and R01 HL127342 to VN, American Heart Association Predoctoral Fellowship (15PRE2190004) to JRS, and NIH/NLHBI NRSA F30 Fellowship (FHL128034A) to JRS.

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