Microvesicles-mediated Cell Communication in Pulmonary Arterial Hypertension

2020 ◽  
Vol 28 ◽  
Author(s):  
Lei Chen ◽  
Ying-Jian Gu ◽  
Ming-Yuan Zhou ◽  
Lin Cheng ◽  
Yun Wang
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Target ◽  
Cell Communication ◽  
Pathological Process ◽  
Bioactive Molecules ◽  
Inflammatory Factors ◽  
Target Cells ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension is one of the chronic diseases that affect the human health. Microvesicles participate in the communication between cells by fusing with the recipient cells to transfer the bioactive molecules, such as lipids, proteins, RNA, etc., to the target cells. Microvesicles are involved in various biological processes, and have the functions of regulating immunity, promoting angiogenesis and so on. Microvesicles derived from various cells may become diagnostic biomarkers or therapeutic targets to the diseases. Therefore, exploring the role of microvesicles-mediated cell communication has become a potential therapeutic target to pulmonary arterial hypertension. Objective: It is to clarify the classification, features and mechanism of microvesicles in cell communication, and to discuss the potential important roles of microvesicles-mediated cell communication in pulmonary arterial hypertension. Results: Inflammation is an important the pathogenesis of pulmonary arterial hypertension. Many studies have shown that microvesicles from different cells can participate in the pathological process of PAH by transferring the inflammatory factors contained in them. Conclusion: Microvesicles-mediated cell communication may become the therapeutic target to pulmonary arterial hypertension.

scholarly journals ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure

2019 ◽  
Vol 125 (10) ◽  
pp. 884-906 ◽  
Author(s):  
Junichi Omura ◽  
Kimio Satoh ◽  
Nobuhiro Kikuchi ◽  
Taijyu Satoh ◽  
Ryo Kurosawa ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Knockout Mice ◽  
Therapeutic Target ◽  
Pulmonary Arterial ◽  
Novel Therapeutic

Rationale: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. Objective: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. Methods and Results: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTS ΔSM22 ). Hypoxia-induced PH was attenuated in ADAMTS ΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTS ΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8 ΔαMHC ). ADAMTS8 ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8 ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. Conclusions: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

scholarly journals Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension

2019 ◽  
Vol 316 (5) ◽  
pp. L723-L737 ◽  
Author(s):  
Sarah E. Hogan ◽  
Maria Pia Rodriguez Salazar ◽  
John Cheadle ◽  
Rachel Glenn ◽  
Carolina Medrano ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Mitochondrial Function ◽  
Therapeutic Potential ◽  
Tca Cycle ◽  
Target Cells ◽  
The Tca Cycle ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O2 consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.

Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

2016 ◽  
Vol 15 (1) ◽  
pp. 12-13
Author(s):  
Adaani E. Frost ◽  
Harrison W. Farber
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Transplantation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Donor Organ ◽  
The Road ◽  
Lung Allocation Score ◽  
Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

An Expanding Role of Biomarkers in Pulmonary Arterial Hypertension

2017 ◽  
Vol 18 (6) ◽  
Author(s):  
Mustafa Yildiz ◽  
Alparslan Sahin ◽  
Michael Behnes ◽  
İbrahim Akin
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial

scholarly journals Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Kyle A. Batton ◽  
Christopher O. Austin ◽  
Katelyn A. Bruno ◽  
Charles D. Burger ◽  
Brian P. Shapiro ◽  
...  
Keyword(s):  
Sex Differences ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial

Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: Role of the peripheral chemoreflex

2021 ◽  
Author(s):  
Marcelle Paula-Ribeiro ◽  
Indyanara C. Ribeiro ◽  
Liliane C. Aranda ◽  
Talita M. Silva ◽  
Camila M. Costa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Early Stage ◽  
Pressure Fluctuations ◽  
Sit To Stand ◽  
Peak Aerobic Capacity ◽  
Pulmonary Arterial ◽  
Peripheral Chemoreflex

The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in non-hypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity (i.e., V̇O2peak); and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptors inhibition) or 21% O2 (control session), while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEIALL at rest (mean ± SD: PAH = 0.5 ± 0.2 vs HA = 0.7 ± 0.1 a.u., P = 0.02) and lower cBRSALL (PAH = 6.8 ± 7.0 vs HA = 9.7 ± 5.0 ms mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇O2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in non-hypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇O2peak suggesting it could be functionally relevant.

Role of amlodipine in preventing and reversing monocrotaline-induced pulmonary arterial hypertension in rats

2004 ◽  
Vol 10 (5) ◽  
pp. S173
Author(s):  
Eiichiro Mawatari ◽  
Minoru Hongo ◽  
Akio Sakai ◽  
Ruan Zonghai ◽  
Fumiaki Ogiwara ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial
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