Pulmonary Artery (PA) Smooth Muscle (SM) Proteins in Postnatal Sheep with High Flow Pulmonary Hypertension (PH). ♦ 146

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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

10.21203/rs.3.rs-155698/v1 ◽

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.

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Cyclooxygenase-2 Acts as an Endogenous Brake on Endothelin-1 Release by Human Pulmonary Artery Smooth Muscle Cells: Implications for Pulmonary Hypertension

Molecular Pharmacology ◽

10.1124/mol.62.5.1147 ◽

2002 ◽

Vol 62 (5) ◽

pp. 1147-1153 ◽

Cited By ~ 21

Author(s):

Stephen J. Wort ◽

Mandy Woods ◽

Timothy D. Warner ◽

Timothy W. Evans ◽

Jane A. Mitchell

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Cyclooxygenase 2 ◽

Endothelin 1 ◽

Pulmonary Artery Smooth Muscle ◽

Human Pulmonary Artery

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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 ◽

10.3390/metabo8040087 ◽

2018 ◽

Vol 8 (4) ◽

pp. 87 ◽

Cited By ~ 2

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.

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