Endothelial Dysfunction In Patients With Idiopathic Pulmonary Arterial Hypertension And Schistosomiasis: The Role Of E-selectin

In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fibrinogen-like protein 2 (FGL2) prothrombinase is an immune coagulant that can cleave prothrombin to thrombin, which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. FGL2 prothrombinase is mainly expressed in endothelial cells and mediates multiple pathological processes. This implies that it may also play a role in PH. In this study, we examined the expression of FGL2 in idiopathic pulmonary arterial hypertension (IPAH) patients, and in monocrotaline-induced rat and hypoxia-induced mouse PH models. Fgl2−/− mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling, and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of FGL2 in PH. We show FGL2 is upregulated in pulmonary vascular endothelium in human IPAH and in two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling, and reduced endothelial dysfunction. In addition, loss of FGL2 downregulated PAR1 (proteinase-activated receptor 1) expression and decreased the overactivation and consumption of platelets in hypoxia-induced PH. These results indicate FGL2 participate in the development of PH and loss of FGL2 could attenuate PH by reducing in situ thrombosis and suppressing PAR1 signaling. Thus we provide evidence that suggests FGL2 prothrombinase presents a potential therapeutic target for clinical treatment of PH. NEW & NOTEWORTHY This is the first study to demonstrate that fibrinogen-like protein 2 (FGL2) participates in the pathological progression of pulmonary hypertension (PH) in human idiopathic pulmonary arterial hypertension, a monocrotaline rat PH model, and a hypoxia mouse PH model. Genetic knockout of Fgl2 significantly limited the development of PH indicated by reduced in situ thrombosis, vascular remodeling, and endothelial dysfunction, and suppressed PAR1 (proteinase-activated receptor 1) signaling and overactivation of platelets on PH. These results suggest FGL2 presents a potential therapeutic target for clinical treatment of PH.

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Role of vascular remodeling markers in the development of osteoporosis in idiopathic pulmonary arterial hypertension

Terapevticheskii arkhiv ◽

10.17116/terarkh201688965-70 ◽

2016 ◽

Vol 88 (9) ◽

pp. 65-70

Author(s):

V A Nevzorova ◽

E A Kochetkova ◽

L G Ugay ◽

Yu V Maistrovskaya ◽

E A Khludeeva

Keyword(s):

Pulmonary Arterial Hypertension ◽

High Risk ◽

Cardiac Index ◽

Arterial Hypertension ◽

Healthy Volunteers ◽

Vascular Remodeling ◽

Serum Levels ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Pulmonary Arterial

Aim. To define the role of circulating biomarkers for the metabolism of collagen and intercellular substance and vascular remodeling in the development of osteoporosis (OP) in idiopathic pulmonary arterial hypertension (IPAH). Materials and methods. Functional hemodynamic parameters, bone mineral density (BMD) in the lumbar spine and femoral neck and the serum levels of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), MMP-9/TIMP-1 complex, C-terminal telopeptide of collagen type 1 (CITP), and endothelin-1 (ET-1) were determined in 27 high-risk IPAH patients and 30 healthy volunteers. Results. OP in IPAH was detected in 50% of the examinees. The serum levels of CITP, MMP-9, TIMP-1, and ET-1 proved to be higher in the high-risk IPAH patients than in the healthy volunteers. There was a direct correlation between BMD and six-minute walk test and an inverse correlation with total pulmonary vascular resistance (TPVR). Serum TMIP-1 levels correlated with cardiac index and TPVR; ET-1 concentrations were directly related to pulmonary artery systolic pressure, cardiac index, and TPVR. Inverse relationships were found between BMD and circulating CITP, MMP-9, TMIP-1, MMP-9/TMIP-1, and ET-1. At the same time, there was only a tendency towards a positive correlation between serum CITP and ET-1 concentrations. Conclusion. The results of the investigation confirm that endothelin system dysregulation plays a leading role in the development of persistent hemodynamic disorders in high-risk IPAH and suggest that it is involved in the development of osteopenic syndrome. Enhanced ET-1 secretion initiates bone loss possibly via activation of connective tissue matrix destruction.

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Role of Hyaluronan and Nitric Oxide in Tissue Injury and Repair in Idiopathic Pulmonary Arterial Hypertension.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a1841 ◽

2009 ◽

Author(s):

M Aytekin ◽

S Haserodt ◽

S Comhair ◽

R Dweik

Keyword(s):

Nitric Oxide ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Tissue Injury ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Pulmonary Arterial ◽

Injury And Repair

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153 Systemic Endothelial Dysfunction in Children with Idiopathic Pulmonary Arterial Hypertension Correlates with Disease Severity

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2012.01.157 ◽

2012 ◽

Vol 31 (4) ◽

pp. S60

Author(s):

D. Friedman ◽

J. Szmuszkovicz ◽

M. Rabai ◽

J.A. Detterich ◽

J. Menteer ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Disease Severity ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Pulmonary Arterial

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

Circulation Research ◽

10.1161/circresaha.119.315398 ◽

2019 ◽

Vol 125 (10) ◽

pp. 884-906 ◽

Cited By ~ 9

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.

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