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.

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.

scholarly journals Profiling the Role of Mammalian Target of Rapamycin in the Vascular Smooth Muscle Metabolome in Pulmonary Arterial Hypertension

2015 ◽  
Vol 5 (4) ◽  
pp. 667-680 ◽  
Author(s):  
Tatiana V. Kudryashova ◽  
Dmitry A. Goncharov ◽  
Andressa Pena ◽  
Kaori Ihida-Stansbury ◽  
Horace DeLisser ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Vascular Smooth Muscle ◽  
Arterial Hypertension ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Pulmonary Arterial

scholarly journals T6 TRAIL is a potential novel therapeutic target in pulmonary arterial hypertension

Thorax ◽  
2011 ◽  
Vol 66 (Suppl 4) ◽  
pp. A3-A3
Author(s):  
A. G. Hameed ◽  
N. D. Arnold ◽  
J. Pickworth ◽  
J. C. Chamberlain ◽  
C. M. H. Newman ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Target ◽  
Pulmonary Arterial ◽  
Novel Therapeutic

Tumour necrosis factor-related apoptosis-inducing ligand is a novel therapeutic target in pulmonary arterial hypertension

The Lancet ◽  
2013 ◽  
Vol 381 ◽  
pp. S47
Author(s):  
Abdul G Hameed ◽  
Nadine D Arnold ◽  
Janet Chamberlain ◽  
Josephine A Pickworth ◽  
Claudia Paiva ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Tumour Necrosis Factor ◽  
Therapeutic Target ◽  
Tumour Necrosis ◽  
Pulmonary Arterial ◽  
Necrosis Factor ◽  
Novel Therapeutic

scholarly journals Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

2020 ◽  
Vol 318 (4) ◽  
pp. H853-H866 ◽  
Author(s):  
Yin Kang ◽  
Guangyan Zhang ◽  
Emma C. Huang ◽  
Jiapeng Huang ◽  
Jun Cai ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Lung Injury ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies. NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.

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.

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