scholarly journals MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (11) ◽  
pp. 4130
Author(s):  
Maria Catalina Gomez-Puerto ◽  
Xiao-Qing Sun ◽  
Ingrid Schalij ◽  
Mar Orriols ◽  
Xiaoke Pan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Umbilical Vein ◽  
Pulmonary Vascular Remodeling ◽  
Protein Levels ◽  
Pulmonary Arterial ◽  
Umbilical Vein Endothelial Cells

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by obstructed pulmonary vasculatures. Current therapies for PAH are limited and only alleviate symptoms. Reduced levels of BMPR2 are associated with PAH pathophysiology. Moreover, reactive oxygen species, inflammation and autophagy have been shown to be hallmarks in PAH. We previously demonstrated that MnTBAP, a synthetic metalloporphyrin with antioxidant and anti-inflammatory activity, inhibits the turn-over of BMPR2 in human umbilical vein endothelial cells. Therefore, we hypothesized that MnTBAP might be used to treat PAH. Human pulmonary artery endothelial cells (PAECs), as well as pulmonary microvascular endothelial (MVECs) and smooth muscle cells (MVSMCs) from PAH patients, were treated with MnTBAP. In vivo, either saline or MnTBAP was given to PAH rats induced by Sugen 5416 and hypoxia (SuHx). On PAECs, MnTBAP was found to increase BMPR2 protein levels by blocking autophagy. Moreover, MnTBAP increased BMPR2 levels in pulmonary MVECs and MVSMCs isolated from PAH patients. In SuHx rats, MnTBAP reduced right ventricular (RV) afterload by reversing pulmonary vascular remodeling, including both intima and media layers. Furthermore, MnTBAP improved RV function and reversed RV dilation in SuHx rats. Taken together, these data highlight the importance of MnTBAP as a potential therapeutic treatment for PAH.

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.

P6008Inhibin Beta-A is a novel gene involved in the development of pulmonary arterial hypertension through inhibiting BMPRII-signaling in endothelial cells

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G R T Ryanto ◽  
K Ikeda ◽  
K Miyagawa ◽  
K Yagi ◽  
Y Suzuki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Gene ◽  
Microarray Analysis ◽  
Knockout Mice ◽  
Vascular Remodeling ◽  
Hypoxia Exposure ◽  
Pulmonary Arterial

Abstract Introduction Pulmonary Arterial Hypertension (PAH) is marked by vascular remodeling process that eventually causes pressure increase. Endothelial cells (EC) dysfunction is known to be a major cause for pulmonary vascular remodeling; however, the molecular mechanism remains to be elucidated. Purpose This study aims to identify novel genes and mechanisms involved in PAH development. Methods We performed DNA microarray analysis using RNA samples isolated from human ECs of various vascular beds (including lung microvessels) and organs (including lung). We subsequently searched for genes highly and specifically expressed in lung microvessels since these genes are likely involved in pulmonary circulation homeostasis maintenance. Once found, we confirmed its expressional changes during hypoxia in ECs and lung tissues. We next analyzed its role in EC functions using human pulmonary artery ECs (hPAECs) by in vitro angiogenesis assay, using both candidate gene overexpression via retrovirus transfection and treatment with its active form using appropriate recombinant protein. To explore the role of candidate gene in PAH development in vivo, we generated EC-specific knockout mice and transgenic mice in which the candidate gene is genetically deleted and activated in ECs, respectively. PAH was induced by chronic hypoxia exposure (10% O2- for 3 weeks). Lastly, to explore the underlying mechanisms, we analyzed expressional alterations in possible signaling pathways in ECs that could relate with the effect of the candidate gene. Results From microarray analysis, we identified inhibin Beta-A (INHBA) as a candidate gene that was highly and specifically expressed in human lung microvascular ECs. INHBA homo-dimerization is known to produce activin A (ActA), a TGF-beta superfamily member. Hypoxia exposure caused significant decrease of INHBA mRNA expression in ECs and mouse lung tissues. Both INHBA overexpression and ActA-treatment in hPAECs caused dramatic reduction of their angiogenic capacities (reduced migration and tube formation capability with increased apoptosis). In vivo, EC-specific INHBA overexpressing mice (VEcad-INHBA-TG) showed exacerbated hypoxia-induced PAH, assessed by higher right ventricular systolic pressure (RVSP) and more severely remodeled pulmonary arteries. By contrast, EC-specific INHBA knockout mice (INHBA-floxed/VEcad-Cre-TG) showed significant amelioration of PAH, shown by reduced RVSP and vascular remodeling. Furthermore, we found that INHBA overexpression and ActA-treatment induced a marked reduction of BMPRII, known to play pivotal roles in PAH, in hPAECs by accelerating its lysosomal degradation. Conclusion We identified a novel gene that is crucially involved in PAH development. INHBA and/or ActA negatively regulates EC functions potentially through its BMPRII-altering capability. Gain- and loss-of-function studies in mice revealed that INHBA pathways are promising therapeutic targets for the treatment of PAH.

scholarly journals MiR-193-3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402097491
Author(s):  
Zhenhua Wu ◽  
Jie Geng ◽  
Yujuan Qi ◽  
Jian Li ◽  
Yaobang Bai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs). To explore the potential mechanism of miR-193-3p in pulmonary arterial hypertension, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and p21-activated protein kinase 4 (PAK4) in the lung samples of PAH patients and paired healthy samples from the healthy subjects in PHA cells and rats were detected by quantitative reverse transcriptase-PCR. Morphological changes in lung tissues were determined using hematoxylin and eosin staining. Right ventricular systolic pressure (RVSP) and ratio of right ventricle to left ventricle plus septum (RV/LV p S) were measured. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, and migration were detected by 3-(4, 5-Dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) flow cytometry, and wound-healing assays, respectively. The protein expressions of PAK4, proliferating cell nuclear antigen (PCNA), P21, p-AKT, and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in pulmonary arterial hypertension, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia condition promoted cell proliferation, migration, and inhibited apoptosis accompanied with increased expressions of PCNA and p-AKT/AKT and decreased expression of P21 in PASMCs. MiR-193-3p overexpression attenuated the effects of hypoxia on PASMCs via downregulating PAK4. Monocrotaline treatment increased p-AKT/AKT and decreased P21 expression and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT, and increased P21 levels via downregulating PAK4 in monocrotaline-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregulating PAK4.

scholarly journals NADPH oxidase-mediated endothelial injury in HIV- and opioid-induced pulmonary arterial hypertension

2020 ◽  
Vol 318 (5) ◽  
pp. L1097-L1108 ◽  
Author(s):  
Stuti Agarwal ◽  
Himanshu Sharma ◽  
Ling Chen ◽  
Navneet K. Dhillon
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Protein S ◽  
Microvascular Endothelial Cells ◽  
Transgenic Rats ◽  
Pulmonary Arterial

We previously demonstrated that the combined exposure of human pulmonary microvascular endothelial cells (HPMECs) to morphine and viral protein(s) results in the oxidative stress-mediated induction of autophagy, leading to shift in the cells from early apoptotic to apoptosis-resistant proliferative status associated with the angioproliferative remodeling observed in pulmonary arterial hypertension (PAH). In this study, we tried to delineate the major source of HIV-1 protein Tat and morphine induced oxidative burst in HPMECs and its consequences on vascular remodeling and PAH in an in vivo model. We observed switch from the initial increased expression of NADPH oxidase (NOX) 2 in response to acute treatment of morphine and HIV-Tat to later increased expression of NOX4 on chronic treatment in the endoplasmic reticulum of HPMECs without any alterations in the mitochondria. Furthermore, NOX-dependent induction of autophagy was observed to play a pivotal role in regulating the endothelial cell survival. Our in vivo findings showed significant increase in pulmonary vascular remodeling, right ventricular systolic pressure, and Fulton index in HIV-transgenic rats on chronic administration of morphine. This was associated with increased oxidative stress in lung tissues and rat pulmonary microvascular endothelial cells. Additionally, endothelial cells from morphine-treated HIV-transgenic rats demonstrated increased expression of NOX2 and NOX4 proteins, inhibition of which ameliorated their increased survival upon serum starvation. In conclusion, this study describes NADPH oxidases as one of the main players in the oxidative stress-mediated endothelial dysfunction on the dual hit of HIV-viral protein(s) and opioids.

scholarly journals Sugen–morphine model of pulmonary arterial hypertension

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401989837
Author(s):  
Stuti Agarwal ◽  
Zachery J. Harter ◽  
Balaji Krishnamachary ◽  
Ling Chen ◽  
Tyler Nguyen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Growth Factor Receptor ◽  
Serum Starvation ◽  
Microvascular Endothelium ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a fatal disease associated with pulmonary vascular remodeling and right ventricular hypertrophy. Pre-clinical animal models that reproduce the human pulmonary arterial hypertension process and pharmacological response to available therapies are critical for future drug development. The most prevalent animal model reproducing many aspects of angioobliterative forms of pulmonary arterial hypertension is the rat Sugen/hypoxia model in which Sugen, a vascular endothelial growth factor receptor antagonist, primarily causes initiation of endothelial injury and later in the presence of hypoxia promotes proliferation of apoptosis-resistant endothelial cells. We previously demonstrated that exposure of human pulmonary microvascular endothelium to morphine and HIV-proteins results in initial apoptosis followed by increased proliferation. Here, we demonstrate that the double-hit of morphine and Sugen 5416 (Sugen–morphine) in rats leads to the development of pulmonary arterial hypertension with significant medial hypertrophy of pre-acinar pulmonary arteries along with neo-intimal thickening of intra-acinar vessels. In addition, the pulmonary smooth muscle and endothelial cells isolated from Sugen–morphine rats showed hyperproliferation and apoptotic resistance, respectively, in response to serum starvation. Our findings support that the dual hit model of Sugen 5416 and morphine provides another experimental strategy to induce significant pulmonary vascular remodeling and development of severe pulmonary arterial hypertension pathology in rats without exposure to hypoxia.

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.

Sign in / Sign up

Export Citation Format

Share Document