scholarly journals Upregulation of Aquaporin 1 Mediates Increased Migration and Proliferation in Pulmonary Vascular Cells From the Rat SU5416/Hypoxia Model of Pulmonary Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Yun ◽  
Nicolas M. Philip ◽  
Haiyang Jiang ◽  
Zion Smith ◽  
John C. Huetsch ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Ventricular Remodeling ◽  
Water Channel ◽  
Hypoxic Exposure ◽  
Mrna Levels ◽  
Vascular Cells ◽  
Cell Hyperplasia ◽  
Aquaporin 1 ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by exuberant vascular remodeling leading to elevated pulmonary arterial pressure, maladaptive right ventricular remodeling, and eventual death. The factors controlling pulmonary arterial smooth muscle cell (PASMC) and endothelial cell hyperplasia and migration, hallmark features of the vascular remodeling observed in PAH, remain poorly understood. We previously demonstrated that hypoxia upregulates the expression of aquaporin 1 (AQP1), a water channel, in PASMCs, and that this upregulation was required for hypoxia-induced migration and proliferation. However, whether the same is true in a model of severe PAH and in pulmonary microvascular endothelial cells (MVECs) is unknown. In this study, we used the SU5416 plus hypoxia (SuHx) rat model of severe pulmonary hypertension, which mimics many of the features of human PAH, to determine whether AQP1 levels were altered in PASMCs and MVECs and contributed to a hyperproliferative/hypermigratory phenotype. Rats received a single injection of SU5416 (20 mg/kg) and then were placed in 10% O2 for 3 weeks, followed by a return to normoxic conditions for an additional 2 weeks. We found that AQP1 protein levels were increased in both PASMCs and MVECs from SuHx rats, even in the absence of sustained hypoxic exposure, and that in MVECs, the increase in protein expression was associated with upregulation of AQP1 mRNA levels. Silencing of AQP1 had no significant effect on PASMCs from control animals but normalized enhanced migration and proliferation observed in cells from SuHx rats. Loss of AQP1 also reduced migration and proliferation in MVECs from SuHx rats. Finally, augmenting AQP1 levels in MVECs from control rats using forced expression was sufficient to increase migration and proliferation. These results demonstrate a key role for enhanced AQP1 expression in mediating abnormal migration and proliferation in pulmonary vascular cells from a rodent model that reflects many of the features of human PAH.

p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice

2011 ◽  
Vol 300 (5) ◽  
pp. L753-L761 ◽  
Author(s):  
Shiro Mizuno ◽  
Herman J. Bogaard ◽  
Donatas Kraskauskas ◽  
Aysar Alhussaini ◽  
Jose Gomez-Arroyo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Left Ventricle ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Hypoxic Exposure ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
The Right

Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.

scholarly journals AB1139 DIAGNOSTICIS AND PROGNOSTICIS SIGNIFICANCE OF CHEST CT EVALUATION OF SMALL PULMONARY VESSELS IN CONNECTIVE TISSUE DISEASES WITH PULMONARY ARTERIAL HYPERTENSION.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1859.1-1860
Author(s):  
Y. Zhang ◽  
N. Zhang ◽  
Y. Zhu ◽  
Q. Wang ◽  
L. Zhou
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Connective Tissue Diseases ◽  
Chest Ct ◽  
Pulmonary Vessels ◽  
Ct Evaluation ◽  
Pulmonary Arterial

Background:Pulmonary arterial hypertension (PAH) is a fatal complication of connective tissue diseases (CTDs). Chest CT has been increasingly used in the evaluation of patients with suspected PH noninvasively but there is a paucity of studies.Objectives:Our study was aimed to investigate the cross-sectional area (CSA) of small pulmonary vessels on chest CT for the diagnosis and prognosis of CTD-PAH.Methods:This retrospective study analyzed the data of thirty-four patients with CTD-PAH who were diagnosed by right heart catheterization (RHC) and underwent chest CT between March 2011 and October 2019. We measured the percentage of total CSA of vessels<5 mm2and 5-10 mm2as a percentage of total lung area (%CSA<5and %CSA5-10) on Chest CT. Furthermore, the association of %CSA with mean pulmonary artery pressure (mPAP) was also investigated. Besides, these patients were followed up until October 2019, and Kaplan-Meier survival curves were generated for the evaluation of prognosis.Results:Patients with CTD-PAH had significantly higher %CSA5-10than CTD-nPAH (p=0.001), %CSA5-10in CTD-S-PAH and IPAH was significantly higher than CTD-LM-PAH and COPD-PH (p<0.01). There was a positive correlation between %CSA5-10and mPAP in CTD-PAH (r=0.447, p=0.008). Considering %CSA5-10above 0.38 as a threshold level, the sensitivity and specificity were found to be 0.824 and 0.706, respectively. Patients with %CSA5-10≥0.38 had a lower survival rate than those with %CSA5-10<0.38 (p=0.049).Conclusion:Quantitative parameter, %CSA5-10on Chest CT might serve a crucial differential diagnostic tool for different types of PH. %CSA5-10≥0.38 is a prognostic indicator for evaluation of CTD-PAH.References:[1]Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177.[2]Siddiqui I, Rajagopal S, Brucker A, et al. Clinical and Echocardiographic Predictors of Outcomes in Patients With Pulmonary Hypertension. Am J Cardiol. 2018;122(5):872-878.[3]Coste F, Dournes G, Dromer C, et al. CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension. Thorax. 2016;71(9):830-837.[4]Freed BH, Collins JD, Francois CJ, et al. MR and CT Imaging for the Evaluation of Pulmonary Hypertension. JACC Cardiovasc Imaging. 2016;9(6):715-732.[5]Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):25S-32S.[6]Zanatta E, Polito P, Famoso G, et al. Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment. Exp Biol Med (Maywood). 2019;244(2):120-131.[7]Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165-175.[8]Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.[9]Thompson AAR, Lawrie A. Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. Trends Mol Med. 2017;23(1):31-45.[10]Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297-309.[11]Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012;122(12):4306-4313.[12]Seeger W, Adir Y, Barbera JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109-116.Acknowledgments:Thanks to all patients involved in this retrospective study. Thanks go to every participant who participated in this study for their enduring efforts in working with participants to complete the study. Thanks to Liangmin Wei for helping us with statistics analysis.Disclosure of Interests:None declared

Abstract 19126: Endothelial-specific Deletion of Prolyl Hydroxylase Domain Protein 2 (PHD2) Results in Severe Pulmonary Hypertension in Mice by Enhancing the HIF2alpha Signaling Pathway

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Haiyang Tang ◽  
Yali Gu ◽  
Ramon Aryon ◽  
Shanshan Song ◽  
Ruby A Fernandez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Normoxic Condition ◽  
Severe Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Domain Protein ◽  
Specific Deletion

Rationale: Sustained pulmonary vasoconstriction and excessive vascular remodeling are major causes of elevated pulmonary vascular resistance which leads to increased pulmonary arterial pressure in patients with pulmonary hypertension. Hypoxic-inducible factor (HIF) and its upstream regulators have been linked to the hypoxia response in vascular remodeling and the development of pulmonary hypertension. In this study, we aimed at defining whether increased HIF1α and/or HIF2α, due to endothelial cell specific deletion of prolyl hydroxylase domain protein 2 (PHD2) under normoxic condition are involved in or required for the initiation and progression of pulmonary hypertension. Methods: PHD2, HIF1α and HIF2α conditional knockout mice were created. Right ventricle systolic pressures (RVSP), right ventricular hypertrophy by RV/(LV+S) ratios, and small pulmonary artery smooth muscle layer thickness were measured. Pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs) were isolated from wild type (WT) or knockout (KO) mice, followed with cell-based assays. Results: We report here that mice with targeted deletion of PHD2 developed severe pulmonary hypertension under normoxic condition. Conditional and inducible deletion of HIF2α in endothelial cells, but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. HIF2α KO mice had significantly lower RVSP, RV/(LV+S) ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia compared to their WT mice. Conclusion: This work shows that the endothelium is responsible for the development of pulmonary hypertension and it demonstrates a crucial role of PHD2/HIF signaling for hypoxic response in pulmonary hypertension. These findings unveil temporally and spatially distinct functions for HIFs in the development of pulmonary hypertension.

scholarly journals HIF2α–arginase axis is essential for the development of pulmonary hypertension

2016 ◽  
Vol 113 (31) ◽  
pp. 8801-8806 ◽  
Author(s):  
Andrew S. Cowburn ◽  
Alexi Crosby ◽  
David Macias ◽  
Cristina Branco ◽  
Renato D. D. R. Colaço ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelium ◽  
Arginase 1

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

Hypoxia- or PDGF-BB-dependent paxillin tyrosine phosphorylation in pulmonary hypertension is reversed by HIF-1α depletion or imatinib treatment

2014 ◽  
Vol 112 (12) ◽  
pp. 1288-1303 ◽  
Author(s):  
Christine Veith ◽  
Dariusz Zakrzewicz ◽  
Bhola Kumar Dahal ◽  
Zoltán Bálint ◽  
Kirsten Murmann ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Vasculature ◽  
Hypoxic Exposure ◽  
Imatinib Treatment ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

SummaryChronic exposure to hypoxia induces a pronounced remodelling of the pulmonary vasculature leading to pulmonary hypertension (PH). The remodelling process also entails increased proliferation and decreased apoptosis of pulmonary arterial smooth muscle cells (PASMC), processes regulated by the cytoskeletal protein paxillin. In this study, we aimed to examine the molecular mechanisms leading to deregulation of paxillin in PH. We detected a time-dependent increase in paxillin tyrosine 31 (Y31) and 118 (Y118) phosphorylation following hypoxic exposure (1 % O2) or platelet-derived growth factor (PDGF)-BB stimulation of primary human PASMC. In addition, both, hypoxia- and PDGF-BB increased the nuclear localisation of phospho-paxillin Y31 as indicated by immunofluorescence staining in human PASMC. Elevated paxillin tyrosine phosphorylation in human PASMC was attenuated by hypoxia-inducible factor (HIF)-1α depletion or by treatment with the PDGF-BB receptor antagonist, imatinib. Moreover, we observed elevated paxillin Y31 and Y118 phosphorylation in the pulmonary vasculature of chronic hypoxic mice (21 days, 10 % O2) which was reversible by imatinib-treatment. PDGF-BB-dependent PASMC proliferation was regulated via the paxillin-Erk1/2-cyclin D1 pathway. In conclusion, we suggest paxillin up-regulation and phosphorylation as an important mechanism of vascular remodelling underlying pulmonary hypertension.Note: Parts of the doctoral thesis of Christine Veith are integrated into this report.

scholarly journals The EYA3 tyrosine phosphatase activity promotes pulmonary vascular remodeling in pulmonary arterial hypertension

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuhua Wang ◽  
Ram Naresh Pandey ◽  
Allen J. York ◽  
Jaya Mallela ◽  
William C. Nichols ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Phosphatase Activity ◽  
Vascular Remodeling ◽  
Tyrosine Phosphatase ◽  
Phosphatase Domain ◽  
Eyes Absent ◽  
Pulmonary Arterial ◽  
Inactivating Mutation

Abstract In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.

scholarly journals 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

2012 ◽  
Vol 113 (9) ◽  
pp. 1343-1352 ◽  
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Arterial ◽  
Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-α signaling

2007 ◽  
Vol 292 (1) ◽  
pp. L125-L133 ◽  
Author(s):  
J. L. Wright ◽  
H. Tai ◽  
R. Wang ◽  
X. Wang ◽  
A. Churg
Keyword(s):  
Pulmonary Hypertension ◽  
Matrix Metalloproteinases ◽  
Cigarette Smoke ◽  
Vascular Remodeling ◽  
Smoke Exposure ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Cigarette Smoke Exposure ◽  
Mrna Levels ◽  
Gelatinase Activity ◽  
Tnf Α

Cigarette smoke exposure causes vascular remodeling and pulmonary hypertension by poorly understood mechanisms. To ascertain whether cigarette smoke exposure affects production of matrix metalloproteinases (MMPs) in the pulmonary vessels, we exposed C57Bl/6 (C57) mice or mice lacking TNF-α receptors (TNFRKO) to smoke daily for 2 wk or 6 mo. Using laser capture microdissection and RT-PCR analysis, we examined gene expression of MMP-2, MMP-9, MMP-12, MMP-13, and tissue inhibitor of metalloproteinase (TIMP-1) and examined protein production by immunohistochemistry for MMP-2, MMP-9, and MMP-12 in small intrapulmonary arteries. At 2 wk, mRNA levels of TIMP-1 and all MMPs were increased in the C57, but not TNFRKO, mice, and immunoreactive protein for MMP-2, MMP-9, and MMP-12 was also increased in the C57 mice. Increased gelatinase activity was identified by in situ and bulk tissue zymography. At 6 mo, only MMP-12 mRNA levels remained increased in the C57 mice, but at a much lower level; however, MMP-2 mRNA levels increased in the TNFRKO mice. We conclude that smoke exposure increases MMP production in the small intrapulmonary arteries but that, with the exception of MMP-12, increased MMP production is transient. MMPs probably play a role in smoke-induced vascular remodeling, as they do in other forms of pulmonary hypertension, implying that MMP inhibitors might be beneficial. MMP production is largely TNF-α dependent, further supporting the importance of TNF-α in the pathogenesis of cigarette smoke-induced lung disease.

Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs

1991 ◽  
Vol 71 (6) ◽  
pp. 2218-2223 ◽  
Author(s):  
S. P. Janssens ◽  
B. T. Thompson ◽  
C. R. Spence ◽  
C. A. Hales
Keyword(s):  
Pulmonary Hypertension ◽  
Guinea Pigs ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Similar Degree ◽  
Similar Tendency ◽  
Pulmonary Arterial ◽  
Medial Thickening

Chronic hypoxia increases pulmonary arterial pressure (PAP) as a result of vasoconstriction, polycythemia, and vascular remodeling with medial thickening. To determine whether preventing the polycythemia with repeated bleeding would diminish the pulmonary hypertension and remodeling, we compared hemodynamic and histological profiles in hypoxic bled (HB, n = 6) and hypoxic polycythemic guinea pigs (H, n = 6). After 10 days in hypoxia (10% O2), PAP was increased from 10 +/- 1 (SE) mmHg in room air controls (RA, n = 5) to 20 +/- 1 mmHg in H (P less than 0.05) but was lower in HB (15 +/- 1 mmHg, P less than 0.05 vs. H). Cardiac output and pulmonary artery vasoreactivity did not differ among groups. Total pulmonary vascular resistance increased from 0.072 +/- 0.011 mmHg.ml-1.min in RA to 0.131 mmHg.ml-1.min in H but was significantly lower in HB (0.109 +/- 0.006 mmHg.ml-1.min). Hematocrit increased with hypoxia (57 +/- 3% in H vs. 42 +/- 1% in RA, P less than 0.05), and bleeding prevented the increase (46 +/- 4% in HB, P less than 0.05 vs. H only). The proportion of thick-walled peripheral pulmonary vessels (53.2 +/- 2.9% in HB and 50.6 +/- 4.8% in H vs. 31.6 +/- 2.6% in RA, P less than 0.05) and the percent medial thickness of pulmonary arteries adjacent to alveolar ducts (7.2 +/- 0.6% in HB and 7.0 +/- 0.4% in H vs. 5.2 +/- 0.4% in RA, P less than 0.05) increased to a similar degree in both hypoxic groups. A similar tendency was present in larger bronchiolar vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jing Chen ◽  
Wen Jiang ◽  
Fei Zhu ◽  
Qiong Wang ◽  
Haiyan Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mitochondrial Function ◽  
Vascular Remodeling ◽  
Control Group ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial ◽  
Toxicological Mechanism ◽  
And Function

Objective. To investigate the role of curcumin in regulating pathogenesis of pulmonary arterial smooth muscle cells (PASMCs) derived from pulmonary arterial hypertension (PAH) model. Methods. Male Sprague Dawley rats were injected with monocrotaline (MCT) to establish the PAH experimental model. The rats were divided into control group, MCT group, and curcumin group. At the end of the study, hemodynamic data were measured to determine pulmonary hypertension. Proliferation ability of PASMCs, a remodeling indicator of pulmonary artery and right ventricle, was detected. In addition, the morphology and function of mitochondria, antiglycolysis and antiproliferation pathways, and genes were also analyzed. Results. Curcumin may function by reversing MCT-mediated pulmonary vascular remodeling in rats. Curcumin effectively improved pulmonary vascular remodeling, promoted PASMC apoptosis, and protected mitochondrial function. In addition, curcumin treatment suppressed the PI3K/AKT pathway in PASMCs and regulated the expression of antiproliferative genes. Conclusion. Curcumin can improve energy metabolism and reverse the process of PAHS. However, there were side effects of curcumin in MCT-induced rats, suggesting that the dosage should be treated with caution and its toxicological mechanism should be further studied and evaluated.

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