Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Avouac, Jérôme; Guignabert, Christophe; Hoffmann-Vold, A. M.; Ruiz, Barbara; Dorfmüller, Peter; Pezet, Sonia; Amar, Olivia; Tu, Ly; Wassenhove, Jérôme Van; Sadoine, Jérémy; Launay, David; Elhaï, Muriel; Cauvet, Anne; Subramaniam, Arun; Resnick, Robert H.; Hachulla, É.; Molberg, Øyvind; Kahan, André; Humbert, Marc; Allanore, Yannick

doi:10.1002/art.40229

Cited by 22 publications

(22 citation statements)

References 54 publications

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“…OPN has also been associated with IPAH (Lorenzen et al, 2011 ) and is therefore not specific for SSc-PAH. Circulating pro-MMP-10 was increased, in SSc-PH patients in comparison with SSc patients without PH or controls, which is consistent with MMP-10 overexpression in the pulmonary arteries of SSc-PAH patients (Avouac et al, 2017 ). The matrix metalloproteinase tissue inhibitor-4 (TIMP-4) may contribute to extracellular matrix deposition in SSc and its level is correlated with elevated SPAP in SSc patients (Gialafos et al, 2008 ).…”

Section: Extracellular Matrix Componentssupporting

confidence: 70%

Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

et al. 2018

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Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.

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Section: Extracellular Matrix Componentssupporting

confidence: 70%

Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

et al. 2018

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“…Current treatments can relieve some PAH symptoms and can slow the progress of PAH in some patients, but they have limited impact on the cellular and molecular mechanisms involved in pathogenic pulmonary vascular remodeling. Among them, it is now well known that the dynamic and unadapted remodeling of extracellular matrix (ECM) remodeling not only leads to qualitative and quantitative changes modulating vessel stiffness but also forms a permissive milieu influencing cell motility, proliferation, apoptosis, and differentiation (2)(3)(4)(5). Consistent with these notions, beneficial effects of different protease inhibitors have been reported in several animal models of pulmonary hypertension (PH) (6)(7)(8)(9)(10).…”

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confidence: 85%

Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension

et al. 2018

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Heightened pulmonary artery smooth muscle cell (PA‐SMC) proliferation and migration and dynamic remodeling of the extracellular matrix are hallmark pathogenic features of pulmonary arterial hypertension (PAH). Pirfenidone (PFD) is an orally bioavailable pyridone derivative with antifibrotic, antiinflammatory, and antioxidative properties currently used in the treatment of idiopathic pulmonary fibrosis. We therefore evaluated the efficacy of curative treatments with PFD in the sugen/hypoxia (SuHx) rat model of severe pulmonary hypertension. Treatment with PFD (30 mg/kg per day by mouth 3 times a day for 3 wk) started 5 wk after sugen injection partially reversed established pulmonary hypertension, reducing total pulmonary vascular resistance and remodeling. Consistent with these observations, we found that continued PFD treatment decreases PA‐SMC proliferation and levels of extracellular matrix deposition in lungs and right ventricles in SuHx rats. Importantly, PFD attenuated the proproliferative and promigratory potentials of cultured PA‐SMCs from patients with idiopathic PAH and their capacity to produce extracellular matrix components. Finally, we found that PFD dose dependently enhanced forkhead box Ol protein levels and its nuclear translocation in cultured idiopathic PAH PA‐SMCs and in PFD‐treated SuHx rats. PFD appears to be a potential therapy for PAH worthy of investigation and evaluation for clinical use in conjunction with current PAH treatments.—Poble, P.‐B., Phan, C., Quatremare, T., Bordenave, J., Thuillet, R., Cumont, A., Huertas, A., Tu, L., Dorf muller, P., Humbert, M., Ghigna, M.‐R., Savale, L., Guignabert, C. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. FASEB J. 33,3670–3679 (2019). http://www.fasebj.org

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“…On the contrary, it has been demonstrated that SSc dermal microvascular endothelial cells exhibit impaired expression of NRP-1 due to Fli1 deficiency, while SSc late-outgrowth EPC-derived endothelial cells have a genuine phenotype characterized by normal expression levels of either Fli1 or NRP-1 ( 77 ). In another study, gene expression profiling of EPC-derived endothelial cells identified matrix metalloproteinase 10 (MMP10) as a novel candidate gene in SSc-associated PH ( 79 ). MMP10 seems to have a predominant role in pathologic conditions related to tissue repair and inflammation ( 80 ) and more recently its role in neovascularization has also been proposed ( 81 , 82 ).…”

Section: Epcs In Sscmentioning

confidence: 99%

“…Circulating serum proMMP10 concentrations were markedly increased in patients with SSc-associated PH compared to SSc patients without PH and healthy controls. Microarray experiments showed that the MMP10 gene was the top upregulated gene in EPC-derived ECs from patients with SSc-associated PH ( 79 ).…”

Section: Epcs In Sscmentioning

confidence: 99%

The Role of Endothelial Progenitors in the Repair of Vascular Damage in Systemic Sclerosis

Papa

Pignataro

2018

Front. Immunol.

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Systemic sclerosis (SSc) is a connective tissue disease characterized by a complex pathological process where the main scenario is represented by progressive loss of microvascular bed, with the consequent progressive fibrotic changes in involved organ and tissues. Although most aspects of vascular injury in scleroderma are poorly understood, recent data suggest that the scleroderma impairment of neovascularization could be related to both angiogenesis and vasculogenesis failure. Particularly, compensatory angiogenesis does not occur normally in spite of an important increase in many angiogenic factors either in SSc skin or serum. Besides insufficient angiogenesis, the contribution of defective vasculogenesis to SSc vasculopathy has been extensively studied. Over the last decades, our understanding of the processes responsible for the formation of new vessels after tissue ischemia has increased. In the past, adult neovascularization was thought to depend mainly on angiogenesis (a process by which new vessels are formed by the proliferation and migration of mature endothelial cells). More recently, increased evidence suggests that stem cells mobilize from the bone marrow into the peripheral blood (PB), differentiate in circulating endothelial progenitors (EPCs), and home to site of ischemia to contribute to de novo vessel formation. Significant advances have been made in understanding the biology of EPCs, and molecular mechanisms regulating EPC function. Autologous EPCs now are becoming a novel treatment option for therapeutic vascularization and vascular repair, mainly in ischemic diseases. However, different diseases, such as cardiovascular diseases, diabetes, and peripheral artery ischemia are related to EPC dysfunction. Several studies have shown that EPCs can be detected in the PB of patients with SSc and are impaired in their function. Based on an online literature search (PubMed, EMBASE, and Web of Science, last updated December 2017) using keywords related to “endothelial progenitor cells” and “Systemic Sclerosis,” “scleroderma vasculopathy,” “angiogenesis,” “vasculogenesis,” this review gives an overview on the large body of data of current research in this issue, including controversies over the identity and functions of EPCs, their meaning as biomarker of SSc microangiopathy and their clinical potency.

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Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Cited by 22 publications

References 54 publications

Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension

The Role of Endothelial Progenitors in the Repair of Vascular Damage in Systemic Sclerosis

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