Supporting data for Matrix metalloproteinase 7 deficiency acts as a protective effect against vascular dysfunction during atherosclerosis

Atherosclerosis is a chronic inflammatory condition characterized by plaque buildup in the arterial lumen and is the underlying cause of cardiovascular disorders such as coronary artery disease (CAD) and stroke (Hurtutise, Jessica et al 2006). The pathogenesis of atherosclerosis involves the buildup of lipids, foam cells and necrotic debris in the intimal layer of the artery. The atherosclerotic plaque at the shoulder region is prone to rupture and when this occurs, blood clots are formed leading to myocardial infarction and death in patients (Lindstedt et al. 1999).

There is a correlation between the induction of matrix metalloproteinase-7 (MMP-7), which is one of the zinc ion (Zn2+)-dependent endopeptidases capable of degrading or remodeling the extracellular matrix (ECM), and the occurrence and development of cardiovascular diseases, especially atherosclerosis (Tuomainen et al. 2014). An increased activity of MMP-7 appears to play an important role in the development of coronary artery disease (Alp et al. 2017), During the formation of atherosclerotic plaque, vascular smooth muscle cells secrete ECM proteins to form a fibrous cap , which helps to maintain plaque stability (Williams et al. 2010). Apoptosis of vascular smooth muscle cells leads to plaque instability in mice with atherosclerosis (von der Thüsen et al. 2002). MMP-7 promotes the cleavage of N-cadherin and the apoptosis of smooth muscle cells, thereby weakening the stability of the fibrous cap and increasing the risk of plaque rupture (Koutsouki et al. 2005; Williams et al. 2010). Additionally, MMP-7, while not being expressed in normal arteries (Halpert et al. 1996), is present in vascular cells and inflammatory macrophages in the atherosclerotic plaque (Burke 2004).

Polymorphisms in the promoter region of the MMP-7 gene that contribute to its expression has been identified: the presence of MMP-7-181A/G allele in hypercholesterolemic patients appeared to be associated with a reduced coronary arterial luminal diameter (Jormsjö et al. 2001). People with MMP-7-181A/G (rs11568818) allele had higher plasma MMP-7 levels and a higher risk of developing atherosclerotic plaques in the femoral artery (Panayiotou et al. 2013; Lee et al. 2007). There was a strong association between high plasma MMP-7 levels and the risk of coronary artery events (Goncalves et al. 2015). Moreover, MMP-7 polymorphisms or increased plasma levels of MMP-7 are related to the reduction of reactive hyperemia index and lower microvascular response (Boumiza et al. 2017). Taken together, these findings suggest that an elevated MMP-7 level may contribute to vascular dysfunction in cardiovascular disease.

Based on these findings, it is hypothesized that up-regulation of MMP-7 expression may lead to endothelial dysfunction. In the present studies, we found that upregulation of MMP-7 in ApoE-deficient mice fed with high-fat diet is associated with the occurrence of endothelium-dependent contractions to acetylcholine, without affecting any endothelium-independent vascular responses in the aorta. Therefore, the protection by MMP-7-deficiency against vascular dysfunction in ApoE-deficient mice may be related to a direct action of MMP-7 on endothelial function. MMP-7 promotes the occurrence of endothelium-dependent contractions in ApoE-deficient mice fed with high-fat diet likely through enhancing the activity of cytosolic phospholipase A2 and upregulating cyclooxygenase-2 to increase endothelial production of prostanoids; this effect can be inhibited by MMP inhibitors.MMP-7-deficiency prevents the activation of NF-κB, a major transcription factor involved in inflammatory responses, and PI3K/AKT as well as MAPK/ERK in ApoE-deficient mice fed with high fat diet.These findings demonstrated that MMP-7 deficiency prevents the development of endothelial dysfunction and vascular inflammation during hyperlipidaemia, thereby inhibiting atherogenesis.