Matrix metalloproteinases and their inhibitors in pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a severe and progressive disease characterised by high pulmonary artery pressure, usually culminating in right heart failure. Current therapeutic approaches in PH largely provide symptomatic relief while the prognosis rate is lower due to the lack of specific molecular targets and the involvement of several factors in the development of PH. Numerous studies have suggested a crucial role of matrix metalloproteinase (MMP) axis during development and disease states, specifically with regard to extracellular matrix remodelling and vascular homeostasis. Increased MMP activity has been demonstrated in experimental animal models of PH, and MMP inhibition has been shown to either attenuate or enhance vascular remodelling. Moreover, several studies emphasise that restoration of deregulated MMPs to physiological MMP/tissue inhibitor of MMPs ratios would potentiate reverse remodelling in PH. This article will highlight the pathophysiological role of MMPs in vascular remodelling and the establishment of PH. In particular, we will focus on the MMP expression and regulation in pulmonary vasculature and pulmonary vascular remodelling. We will also provide an overview of recent clinical and experimental findings and their impact on achieving maximum reversal of PH, as well as current issues and future perspectives.

Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

“…Therefore, we can conclude that chymase-TGF-β1 axis may contribute to pathogenesis of PH associated with lung fibrosis. Additionally, impaired function of the MMP system is also implicated in the context of PH and lung fibrosis, as recently reviewed [22,23]. TCHOUGOUNOVA et al [6] showed a key role of chymase in the activation of inactive pro-MMP-2 and -9.…”

“…Among MC mediators, the chymase may be of particular interest in the context of PH and IPF, owing to its function in activation and processing of transforming growth factor (TGF)-β, endothelin (ET)-1, angiotensin II, interleukins (IL)-1 and IL-18, matrix metalloproteinases (MMP)-2 and 9, and potential involvement in collagen synthesis [5][6][7][8][9][10][11][12][13][14][15][16]. Following this knowledge, it is worth noting that most of the above mentioned molecular mediators/ signalling pathways are suggested to be important culprits in PH and IPF pathologies, thus indicating the potential link between chymase and these diseases [5,[17][18][19][20][21][22][23][24][25][26][27]. Furthermore, it has been described that MCs expressing chymase are indeed altered in PH [28][29][30].…”

Roles of the ERK1/2 and PI3K/PKB signaling pathways in regulating the expression of extracellular matrix genes in rat pulmonary artery smooth muscle cells

“…Previous studies have found that many factors play roles in the matrix deposition process, such as hypoxia 1,2 , ANG II , and that some of these factors can coordinate with each other [14][15] . These factors also play important roles in cell proliferation and migration, as well as the synthesis and secretion of ECM proteins in PAH-PVR.…”

Protective Effects of Bone Marrow-Derived Endothelial Progenitor Cells and <b><i>Houttuynia Cordata</i></b> in Lipopolysaccharide-Induced Acute Lung Injury in Rats

“…Consistent with their study, we also found that HC could inhibit inflammatory reactions in ALI. The MMP axis is known to play a crucial role in extracellular matrix remodeling and vascular homeostasis [28]. Early studies showed that increased MMP activity and expression enhanced vascular remodeling in ALI [29,30].…”