scholarly journals The Shared Pathogenesis of Pulmonary Artery Hypertension

2018 ◽  
Vol 4 (1) ◽  
pp. 22 ◽  
Author(s):  
Anggoro Budi Hartopo ◽  
Lucia Kris Dinarti
Keyword(s):  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Treatment Approach ◽  
Inflammatory Cells ◽  
Pulmonary Artery Hypertension ◽  
Pulmonary Tissue ◽  
Pulmonary Wedge Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Cellular Components ◽  
Wedge Pressure

Pulmonary artery hypertension is defined as an increased in pulmonary artery pressureexceeding 25 mmHg with normal pulmonary wedge pressure. The pathogenesis of pulmonaryartery hypertension involves interaction among vascular, cellular and biomarker componentsin the pulmonary tissue; with eventual result is elevated pulmonary artery pressure. Vascularcomponents are remodeling of intimal, medial and adventitial layers. Cellular components areplayed by apoptosis-resistant endothelial cells, proliferative-prone pulmonary artery smoothmuscle cells, fibroblasts and inflammatory cells. The functional biomarkers are produced andmediated by these cellular changes, mainly endothelin-1, thromboxane, serotonin, nitric oxide,and prostacyclin. The pulmonary vascular remodeling in pulmonary artery hypertension arediverse and may present in various severity based on underlying etiology. Understanding theshared pathogenesis in pulmonary artery hypertension is of paramount importance in order toimprove the disease management and treatment approach.

NPS2143 Modulates the Phenotypic Switching of PASMCs by Inhibiting Autophagy in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Wang L ◽  
◽  
Shao H ◽  
Che B ◽  
Wang N ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Western Blot ◽  
Vascular Remodeling ◽  
Pulmonary Artery Hypertension ◽  
Phenotypic Switching ◽  
Pulmonary Vascular Remodeling

Background and Objectives: Pulmonary Artery Hypertension (PAH) is considered as a malignant tumor in cardiovascular disease. Our previous study found that Calcium-Sensing Receptor (CaSR) is involved in pulmonary vascular remodeling in hypoxic pulmonary hypertension (HPH). However, the relationship of Pulmonary Artery Smooth Muscle Cell (PASMC) phenotypic switching, proliferation, and autophagy in CaSR-related HPH remain unclear. The purpose of this study was to detect the role of a CaSR antagonist, NPS2143, on the vascular remodeling by autophagy modulation under hypoxia. Methods: Hypoxic rat PAH model were simulated in vivo. Meanwhile, mean Pulmonary Artery Pressure (mPAP) was measured while RVI, WT%, and WA% indices were calculated. Immunohistochemistry and Western blot were used to detect phenotypic switching and cell proliferation in pulmonary arteriole. Cell viability was determined in vitro by CCK8 and cell cycle. Cell proliferation, phenotypic switching, autophagy level and PI3K/Akt/mTOR pathways were investigated in human PASMCs through mRNA or Western blot methods. Results: Rats with hypoxic-induced PAH had an increased mPAP, RVI, WT% and WA%. Moreover, expression of CaSR was significantly increased, followed by activation of autophagy (increased LC3b and decreased p62), phenotypic switching of PASMCs (reduced calponin, SMA-a and increased OPN) and pulmonary vascular remodeling. However, NPS2143 weakened these hypoxic effects. The results using hypoxic-induced human PASMCs confirmed that NPS2143 suppressed autophagy and reversed phenotypic switching in vitro by inhibiting PI3K/Akt/mTOR pathways. Conclusions: Our study demonstrates that NPS2143 was conducive to inhibit the proliferation and reverse phenotypic switching of PASMCs by regulating autophagy levels in HPH and vascular remodeling.

Abstract 19236: Effect of Continuous Flow Left Ventricular Assist Device on Diastolic Pulmonary Artery Pressure-to-Pulmonary Capillary Wedge Pressure Gradient in End Stage Heart Failure Patients with Pulmonary Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Thenappan Thenappan ◽  
Rebecca Cogswell ◽  
Forum Kamdar ◽  
Christopher Holley ◽  
Laura Harvey ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Continuous Flow ◽  
Left Ventricular ◽  
Ventricular Assist ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Capillary ◽  
Left Ventricular Assist ◽  
End Stage ◽  
Wedge Pressure

Background: Continuous flow left ventricular assist devices (LVAD) reduces transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) in end-stage HF patients with pulmonary venous hypertension (PVH). However, TPG and PVR are flow dependent and may not reflect intrinsic pulmonary vascular remodeling. Diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient (DPG) has been shown to more accurately reflect pulmonary vascular remodeling. Objective: We sought to evaluate the effect of LVAD on DPG in end-stage HF patients with PVH (mPAP > 25 mm Hg and PCWP > 15 mm Hg). Methods: We retrospectively reviewed clinical and hemodynamic data on 116 end-stage HF patients with PVH who underwent LVAD implantation and analyzed changes in DPG between pre- and first post-LVAD right heart catheterization (RHC). Results: The mean age was 55 ± 14 years and 78% were males. Of the 116 patients, 83 patients had pre-LVAD DPG 7 mm Hg (Combined post-and pre-capillary PVH). The median duration between the pre-and post-LVAD RHC was 147 (IQR: 106-302) days. Table below compares pre-and post-LVAD hemodynamics. In patients with combined post-and pre-capillary PVH, LVAD therapy significantly decreased DPG (9 ± 4 vs. 6 ± 6; P<0.001). However, 42% of these patients did not lower DPG to <7 mmHg with LVAD therapy (non-responders). On multivariate regression, higher pre-LVAD DPG was the only independent factor associated with non-responders. Pre-LVAD DPG >8 mm Hg had 77% sensitivity and 88% specificity for identifying non-responders (AUC 0.82). Conclusion: Although DPG decreased after LVAD therapy, it remained significantly elevated (>7mm Hg) in a subset of patients with combined post-and pre-capillary PVH. DPG >8 mm Hg is significantly associated with non-response to LVAD therapy. Additional studies are warranted to assess the impact of these findings on outcomes.

α-Solanine reverses pulmonary vascular remodeling and vascular angiogenesis in experimental pulmonary artery hypertension

2017 ◽  
Vol 35 (12) ◽  
pp. 2419-2435 ◽  
Author(s):  
Xiaowei Nie ◽  
Youai Dai ◽  
Jianxin Tan ◽  
Yuan Chen ◽  
Guowei Qin ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Pulmonary Artery Hypertension ◽  
Pulmonary Vascular Remodeling

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.

Hypoxia-Induced Changes in the Mechanical Properties of the Mouse Pulmonary Artery

2003 ◽  
Author(s):  
Ryan W. Kobs ◽  
Nidal E. Muvarak ◽  
Naomi C. Chesler
Keyword(s):  
Mechanical Properties ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Hypobaric Hypoxia ◽  
Vessel Wall ◽  
Main Pulmonary Artery ◽  
Collagen Content ◽  
Pulmonary Vascular Remodeling ◽  
Induced Changes

Hypobaric hypoxia produces pulmonary hypertension in mice which causes pulmonary vascular remodeling. To study the biomechanics of this process, mice were exposed to hypoxia for 0-(control), 10-, and 15-days. Using a pressurized arteriograph system, mechanical properties of the main pulmonary artery were measured and compared to the biological changes in the vessel wall measured histologically. 10- and 15-day hypoxic vessels were significantly stiffer when compared to 0-day vessels. This stiffness correlated with greater elastin and collagen content in the vessel wall.

scholarly journals Calpain-2 activates Akt via TGF-β1-mTORC2 pathway in pulmonary artery smooth muscle cells

2016 ◽  
Vol 311 (1) ◽  
pp. C24-C34 ◽  
Author(s):  
Prasanna Abeyrathna ◽  
Laszlo Kovacs ◽  
Weihong Han ◽  
Yunchao Su
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Collagen Synthesis ◽  
Pulmonary Vascular Remodeling ◽  
Calpain 2 ◽  
Pulmonary Artery Smooth Muscle

Calpain is a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases. Akt is a serine/threonine kinase that belongs to AGC kinases and plays important roles in cell survival, growth, proliferation, angiogenesis, and cell metabolism. Both calpain and Akt are the downstream signaling molecules of platelet-derived growth factor (PDGF) and mediate PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. We found that inhibitions of calpain-2 by using calpain inhibitor MDL28170 and calpain-2 small interfering RNA attenuated Akt phosphorylations at serine-473 (S473) and threonine-308 (T308), as well as collagen synthesis and cell proliferation of PASMCs induced by PDGF. Overexpression of calpain-2 in PASMCs induced dramatic increases in Akt phosphorylations at S473 and T308. Moreover, knockout of calpain attenuated Akt phosphorylations at S473 and T308 in smooth muscle of pulmonary arterioles of mice with chronic hypoxic pulmonary hypertension. The cell-permeable-specific transforming growth factor (TGF)-β receptor inhibitor SB431542 attenuated Akt phosphorylations at both S473 and T308 induced by PDGF and by overexpressed calpain-2 in PASMCs. Furthermore, SB-431452 and knocking down activin receptor-like kinase-5 significantly reduced PDGF-induced collagen synthesis and cell proliferation of PASMCs. Nevertheless, neutralizing extracellular TGF-β1 using a cell-impermeable TGF-β1 neutralizing antibody did not affect PDGF-induced Akt phosphorylations at S473 and T308. Furthermore, inhibition of mammalian target of rapamycin complex 2 (mTORC2) by knocking down its component protein Rictor prevented Akt phosphorylations at S473 and T308 induced by PDGF and by overexpressed calpain-2. These data provide first evidence supporting that calpain-2 upregulates PDGF-induced Akt phosphorylation in pulmonary vascular remodeling via an intracrine TGF-β1/mTORC2 mechanism.

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