Matrix metalloproteinase 7 in diagnosis and differentiation of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension is a severe disease for which diagnosis often is delayed. Matrix metalloproteinases have been suggested to play a role in vascular remodeling and pulmonary hypertension development. Our aim was therefore to investigate the potential role of matrix metalloproteinases as biomarkers in diagnosis and differentiation of pulmonary arterial hypertension in relation to various causes of dyspnea and pulmonary hypertension. Using proximity extension assays, 10 matrix metalloproteinases and associated proteins were analyzed in venous plasma from healthy controls (n = 20), as well as patients diagnosed with pulmonary arterial hypertension (n = 48), chronic thromboembolic pulmonary hypertension (n = 20), pulmonary hypertension due to heart failure with preserved (n = 33) or reduced (n = 36) ejection fraction, and heart failure with reduced ejection fraction and heart failure with preserved ejection fraction without pulmonary hypertension (n = 15). Plasma levels of matrix metalloproteinase-2, -7, -9, -12 and TIMP-4 were elevated (p < 0.01) in pulmonary arterial hypertension compared to controls. Plasma levels of matrix metalloproteinase-7 were furthermore lower (p < 0.0081) in pulmonary arterial hypertension than in all the other disease groups, but higher compared to controls (p < 0.0001). Receiver operating characteristic analysis of matrix metalloproteinase-7 resulted in sensitivity of 58.7% and a specificity of 83.3% for detecting pulmonary arterial hypertension among the other disease groups. Plasma matrix metalloproteinase-7 may provide a potential new diagnostic tool to differentiate pulmonary arterial hypertension from other causes of dyspnea, including heart failure with or without pulmonary hypertension and healthy controls. Matrix metalloproteinase-7 may furthermore be involved in the development of pulmonary hypertension and pulmonary arterial hypertension. Future studies investigating the clinical usefulness of matrix metalloproteinase-7 in the differentiation and earlier diagnosis of pulmonary arterial hypertension, as well as its relationship to pulmonary arterial hypertension pathogenesis, are encouraged.

Endothelial Basement Membrane Components and Their Products, Matrikines: Active Drivers of Pulmonary Hypertension?

“…Numerous studies have investigated the role of matrix degrading proteases and their inhibitors in detail [ 99 ] and the altered expression and activity of MMPs [ 167 ] (MMP-2 [ 221 , 222 ], -7 [ 223 ], -9,-10 [ 5 ], -19 [ 5 ]), ADAMs (ADAM17, ADAM33) [ 5 ], cathepsins (Cath S [ 224 ], Cath L [ 214 ]) and TIMPs (TIMP1 and TIMP3) [ 5 ] has been strongly connected with vascular and ECM remodeling. Several of those enzymes are highly abundant in certain inflammatory cells such as monocytes, macrophages, neutrophils, or mast cells and are often upregulated upon immune cell activation [ 220 ].…”

Adaptation to 5 weeks of intermittent local vascular pressure increments; mechanisms to be considered in the development of primary hypertension?

“…Conceivably, this might suggest a pressure-induced uptake of MMP-7, although its underlying mechanisms and functional consequences remains to be investigated; we have found no accounts in the literature of such pressure-induced MMP-7 uptake. Regardless, increasing evidence implicate MMP-7 in the regulation of vascular tone, tissue remodeling, and the initiation of fibrotic and hypertrophic cascades associated with hypertension (17,(20)(21)(22)(41)(42)(43)(44). In spontaneous hypertensive rats, simultaneous knockdown of MMP-7 and tumor necrosis factor-a-converting enzyme attenuated ANG II-induced hypertension as well as the development of cardiac hypertrophy and fibrosis (17,(20)(21)(22).…”

Plasma proteoglycan prolargin in diagnosis and differentiation of pulmonary arterial hypertension

“…9 In a recent study, we found that plasma levels of matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, MMP-12, and tissue inhibitor of metalloproteinase-4 were elevated in PAH compared with healthy controls. 11 Plasma levels of MMP-7 were furthermore lower in PAH compared with chronic thrombo-embolic pulmonary hypertension (CTEPH), as well as HF with preserved or reduced ejection fraction (EF), with or without PH. Future studies investigating the relationship between MMP-7 and PAH pathogenesis, pulmonary vascular remodelling, and congestion, as well as its clinical usefulness in differentiation and earlier diagnosis of PAH, were urged for.…”

“…Future studies investigating the relationship between MMP-7 and PAH pathogenesis, pulmonary vascular remodelling, and congestion, as well as its clinical usefulness in differentiation and earlier diagnosis of PAH, were urged for. 11 Similarly, proteoglycans have a great influence on ECM development and signalling 12,13 and are known to play an important part in ECM remodelling in heart disease. 14 For instance, decorin interacts with transforming growth factor-β, limiting pulmonary fibrosis, whereas glypican-1 is involved in flow-induced endothelial nitric oxide synthase activation.…”

“…In a recent study, we found that plasma levels of matrix metalloproteinase (MMP)‐2, MMP‐7, MMP‐9, MMP‐12, and tissue inhibitor of metalloproteinase‐4 were elevated in PAH compared with healthy controls 11 . Plasma levels of MMP‐7 were furthermore lower in PAH compared with chronic thrombo‐embolic pulmonary hypertension (CTEPH), as well as HF with preserved or reduced ejection fraction (EF), with or without PH.…”