Enhance Smooth Muscle Cells Apoptosis Associated With Pulmonary Arterial Remodeling in Dogs Affected With Pulmonary Hypertension Secondary to Degenerative Mitral Valve Disease

2021 ◽  
Author(s):  
Siriwan Sakarin ◽  
Anudep Rungsipipat ◽  
Sirilak Disatian Surachetpong
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Mitral Valve ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Mitral Valve Disease ◽  
Caspase 3 ◽  
Muscle Cells ◽  
Pulmonary Arterial ◽  
Medial Thickening

Abstract Background: Degenerative mitral valve disease (DMVD) is the most common cause of pulmonary hypertension (PH) in dogs. Medial thickening of the pulmonary artery is a major histopathological change in PH. A decrease in apoptosis of pulmonary arterial smooth muscle cells (SMCs) may be the cause of medial thickening. This study aimed to demonstrate the expression of apoptosis molecules in the pulmonary artery of dogs affected with PH secondary to DMVD (DMVD+PH) compared to DMVD without PH (DMVD) and healthy dogs (control). Lung samples were collected from three groups including control (n=5), DMVD (n=7) and DMVD+PH (n=7) groups. Masson trichrome and apoptotic proteins including Bax, Bcl2 and caspase-3 and -8, were stained. Results: The medial thickness in the DMVD and DMVD+PH groups was greater than in the control group and it was greatest in the DMVD+PH group. Bax, Bcl2 and caspase-3 and -8 were expressed mainly in the medial layer of the pulmonary artery. The percentages of Bax and caspase-3 and -8 positive cells were higher in the DMVD group compared to the DMVD+PH group, whereas the percentage of Bcl2-positive cells was increased in the DMVD and DMVD+PH groups. These findings suggested that apoptosis of pulmonary arterial SMCs occurred mainly in the DMVD group and decreased dramatically in the DMVD+PH group. Conclusions: An increase in the medial thickness in dogs affected with PH secondary to DMVD may occur due to a decrease in apoptosis of pulmonary arterial SMCs.

scholarly journals Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E

Metabolites ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 87 ◽  
Author(s):  
Abdulwahab Alamri ◽  
Abdulhadi Burzangi ◽  
Paul Coats ◽  
David Watson
Keyword(s):  
Reactive Oxygen Species ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
High Glucose ◽  
Muscle Cells ◽  
Oxygen Species ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary arterial hypertension (PAH) is a multi-factorial disease characterized by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Excessive reactive oxygen species (ROS) formation resulted in alterations of the structure and function of pulmonary arterial walls, leading to right ventricular failure and death. Diabetes mellitus has not yet been implicated in pulmonary hypertension. However, recently, variable studies have shown that diabetes is correlated with pulmonary hypertension pathobiology, which could participate in the modification of pulmonary artery muscles. The metabolomic changes in PASMCs were studied in response to 25 mM of D-glucose (high glucose, or HG) in order to establish a diabetic-like condition in an in vitro setting, and compared to five mM of D-glucose (normal glucose, or LG). The effect of co-culturing these cells with an ideal blood serum concentration of cholecalciferol-D3 and tocopherol was also examined. The current study aimed to examine the role of hyperglycemia in pulmonary arterial hypertension by the quantification and detection of the metabolomic alteration of smooth muscle cells in high-glucose conditions. Untargeted metabolomics was carried out using hydrophilic interaction liquid chromatography and high-resolution mass spectrometry. Cell proliferation was assessed by cell viability and the [3H] thymidine incorporation assay, and the redox state within the cells was examined by measuring reactive oxygen species (ROS) generation. The results demonstrated that PASMCs in high glucose (HG) grew, proliferated faster, and generated higher levels of superoxide anion (O2·−) and hydrogen peroxide (H2O2). The metabolomics of cells cultured in HG showed that the carbohydrate pathway, especially that of the upper glycolytic pathway metabolites, was influenced by the activation of the oxidation pathway: the pentose phosphate pathway (PPP). The amount of amino acids such as aspartate and glutathione reduced via HG, while glutathione disulfide, N6-Acetyl-L-lysine, glutamate, and 5-aminopentanoate increased. Lipids either as fatty acids or glycerophospholipids were downregulated in most of the metabolites, with the exception of docosatetraenoic acid and PG (16:0/16:1(9Z)). Purine and pyrimidine were influenced by hyperglycaemia following PPP oxidation. The results in addition showed that cells exposed to 25 mM of glucose were oxidatively stressed comparing to those cultured in five mM of glucose. Cholecalciferol (D3, or vitamin D) and tocopherol (vitamin E) were shown to restore the redox status of many metabolic pathways.

Exosomes Derived from Human Pulmonary Artery Endothelial Cells Shift the Balance between Proliferation and Apoptosis of Smooth Muscle Cells

Cardiology ◽  
2017 ◽  
Vol 137 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Lin Zhao ◽  
Hui Luo ◽  
Xiaohui Li ◽  
Tangzhiming Li ◽  
Jingni He ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Apoptosis Resistance ◽  
Proliferation And Apoptosis ◽  
Pulmonary Arterial ◽  
Human Pulmonary Artery

Background: The overproliferation of pulmonary vascular cells is noted in pulmonary hypertension. The role of exosomes from pulmonary artery endothelial cells (PAEC) in the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMC) remains unclear. Methods: Exosomes were isolated and purified from the culture medium of PAEC using a commercial kit. Lipopolysaccharide (LPS), hypoxia, and hydrogen peroxide were utilized to induce PAEC injury. Coculture of PAEC and PASMC was conducted using Transwell plates, and GW4869 was applied to inhibit exosome release. The proliferation and apoptosis level of PASMC was assayed by MTT assay, apoptosis staining, and cleaved caspase-3 immunoblotting. Plasma exosomes were isolated by differential ultracentrifugation. Results: LPS or hypoxia enhance exosome release from PAEC. Release of PAEC-derived exosomes positively correlates with LPS concentration. The coculture of LPS-disposed PAEC with PASMC leads to overproliferation and apoptosis resistance in PASMC, and the exosome inhibitor GW4869 can partly cancel out this effect. Exosomes derived from PAEC could be internalized into PASMC, and thus promote proliferation and induce apoptosis resistance in PASMC. Idiopathic pulmonary arterial hypertension patients exhibit a higher circulation level of endothelium-derived exosomes. Conclusions: Inflammation and hypoxia could induce PAEC to release exosomes. PAEC- derived exosomes are involved in overproliferation and apoptosis resistance in PASMC, by which they may contribute to the pathogenesis of pulmonary hypertension.

scholarly journals A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells Is the Cell of Origin for Occlusive Pulmonary Vascular Lesions

Circulation ◽  
2020 ◽  
Vol 142 (16) ◽  
pp. 1545-1561
Author(s):  
Lea C. Steffes ◽  
Alexis A. Froistad ◽  
Adam Andruska ◽  
Mario Boehm ◽  
Madeleine McGlynn ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Muscle Cells ◽  
Neointima Formation ◽  
Cell Of Origin ◽  
Medial Thickening

Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow because of medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment; however, our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited. Methods: We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathological features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging, and staged pharmacological inhibition, we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation. Results: Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous, and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension. Conclusions: This work describes the first nongenetically driven murine model of pulmonary hypertension (PH) that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral, and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiological measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.

Abstract 13027: Periostin Cre-mediated Hypoxia-inducible Transfroming Growth Factor-β Receptor Deletion in Pulmonary Artery Attenuates the Progression of Pulmonary Arterial Hypertension in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mitsuru Seki ◽  
Norimichi Koitabashi ◽  
Hirokazu Arakawa ◽  
Masahiko Kurabayashi
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Right Ventricular ◽  
Muscle Cells ◽  
Wild Type ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle ◽  
Β Receptor

Introduction: Mutations in the bone morphogenetic protein type II receptor, transforming growth factor-β (TGF-β) receptor superfamily member, are responsible for heritable pulmonary arterial hypertension (PAH). Although this mutation is associated with TGF-β signal activation, the precise role of TGF-β signaling still remains uncertain in pathogenesis of PAH. Under hypoxic condition, Periostin(Pn) which usually expresses in fibroblasts protein has been shown to express on vascular smooth muscle cell. Therefore, Pn-Cre-loxP system may work as conditional inhibition in hypoxic pulmonary arterial smooth muscle cells. Methods: We established TGF-β type I receptor knockout mice specifically in periostin expressing cell (PnCre/Alk5flox model mice). A mouse model of hypoxia-induced PAH was used for this study. We evaluated right ventricular systolic pressure, function, hypertrophy, and vascular remodeling of pulmonary artery after 3 weeks of exposure to 10% of oxygen. Results: Those mice were induced proliferation of pulmonary arterial smooth muscle cells and perivascular fibrotic change, causing pulmonary hypertension. Right ventricular pressure measured by pressure catheter was significantly decreased in PnCreAlk5flox model mice compared with wild-type mice (44.8±7.8 vs 55.0±9.7mmHg, p<0.05). Right ventricular function and right ventricular weight showed no significant difference between both mice. Histological analysis revealed inhibition of medial thickening of pulmonary artery and perivascular fibrotic change in PnCreAlk5flox model mice compared with wild-type mice (% muscularization of pulmonary artery ; 52.0±14.3 vs 78.4±11.5%, p<0.05). Conclusions: These results indicate that TGF-β signaling in fibroblasts and smooth muscle cells has a critical role on pathogenesis of PAH, suggesting the usefulness of therapy by targeting TGF-β signaling.

scholarly journals LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension

2019 ◽  
Vol 1865 (6) ◽  
pp. 1604-1616 ◽  
Author(s):  
Marius M. Zucker ◽  
Lukasz Wujak ◽  
Anna Gungl ◽  
Miroslava Didiasova ◽  
Djuro Kosanovic ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Pulmonary Artery Smooth Muscle ◽  
Synthetic Phenotype
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