Chapter Eight - Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease
Introduction
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteases with multiple roles in tissue remodeling and degradation of various proteins in the extracellular matrix (ECM). MMPs promote cell proliferation, migration, and differentiation and could play a role in angiogenesis, cell apoptosis, and tissue repair. MMPs may also affect bioactive molecules on the cell surface and modulate various cellular and signaling pathways. Alterations in MMP expression and activity occur in normal biological processes, e.g., during pregnancy and wound healing, but have also been observed in cardiovascular diseases such as atherosclerosis, aneurysms, and chronic venous disease.
In this chapter, we will use data reported in PubMed and other scientific databases as well as data from our laboratory to provide a general overview of the biochemical and biological properties of MMPs with emphasis on MMP structure, tissue distribution, and protein substrates. We will also discuss the regulation of MMP activity by endogenous tissue inhibitors of metalloproteinases (TIMPs) and other synthetic MMP inhibitors. We will then describe specific classes of MMPs and provide examples of their role in cardiovascular diseases. We will conclude the chapter by highlighting the potential benefits of MMPs as biomarkers and therapeutic targets in cardiovascular conditions. Additional information regarding specific MMP functions can be found in other reports (Kucukguven and Khalil, 2013, MacColl and Khalil, 2015, Mittal et al., 2016, Raffetto and Khalil, 2008).
Section snippets
MMP Structure
MMPs were first identified as a collagen proteolytic activity that causes ECM protein degradation during resorption of the tadpole tail (Gross & Lapiere, 1962). MMPs are now grown to a large family of endopeptidases or matrixins that belong to the metzincins superfamily of proteases. MMPs are highly homologous, multidomain, zinc (Zn2 +)-containing metalloproteinases that degrade various protein components of ECM. The MMP family shares a common core structure. Typically MMPs consist of a
Sources and Tissue Distribution of MMPs
MMPs are produced by multiple tissues and cells (Table 1). MMPs are secreted by connective tissue, proinflammatory, and uteroplacental cells including fibroblasts, osteoblasts, endothelial cells, vascular smooth muscle (VSM), macrophages, neutrophils, lymphocytes, and cytotrophoblasts.
Dermal fibroblasts and leukocytes are major sources of MMPs, especially MMP-2 (Saito et al., 2001), and platelets are important sources of MMP-1, MMP-2, MMP-3, and MMP-14 (Seizer & May, 2013). In general, MMPs are
MMP Activation
MMPs are regulated at multiple levels including mRNA expression, activation of the proenzyme to the active form, and the generally counteracting inhibitory actions of endogenous TIMPs. MMPs are synthesized as pre-proMMPs, from which the signal peptide is removed during translation to generate proMMPs. In these zymogens or proMMPs, the cysteine from the propeptide PRCGXPD “cysteine switch” motif coordinates with the catalytic Zn2 + to keep the proMMP in a latent inactive form (Nagase et al., 2006
MMP Substrates
The ECM is composed of fibers, proteoglycans, and polysaccharides. Fibers are largely glycoproteins and include collagen, elastin, laminin, fibronectin, vitronectin, aggrecan, entactin, fibrin, and tenascin. Collagen is the main ECM protein. Elastin is not glycosylated and provides plasticity and flexibility to certain tissues particularly the arteries, lungs, and skin. Laminin is localized in the basal lamina of the epithelium. Fibronectin is used by cells to bind to ECM and can modulate the
Tissue Inhibitors of Metalloproteinases
MMPs are inhibited by both endogenous and exogenous inhibitors. TIMPs are endogenous MMP inhibitors that bind MMPs in a 1:1 stoichiometry (Fig. 3; Bode et al., 1999, Nagase et al., 2006). TIMPs have an N-terminal domain (125 aa) and a C-terminal domain (65 aa), each containing three disulfide bonds. The N-terminal domain folds as a separate unit and is capable of inhibiting MMPs (Murphy et al., 1991, Williamson et al., 1990). The Cys1 is important for chelating the active site Zn2 + with its
Other Biological and Pleiotropic MMP Inhibitors
In addition to endogenous TIMPs, α2-macroglobulin is another endogenous MMP inhibitor found in blood and tissue fluids. Human α2-macroglobulin is a glycoprotein consisting of four identical subunits and a wide-spectrum proteinase inhibitor that inhibits most endopeptidases including MMPs, by entrapping them within the macroglobulin. The complex is then rapidly internalized and cleared by endocytosis via low-density lipoprotein receptor-related protein-1 (Strickland et al., 1990).
Other
Synthetic MMP Inhibitors
Divalent ions can influence MMP release and activity. Cu2 + ion decreases the secretion of MMP-2 (Guo et al., 2005). Deep seawater components such as Cu2 +, Mg2 +, and Mn2 + inhibit proliferation and migration of cultured rat aortic smooth muscle cells by inhibiting not only ERK1/2 and MAPK kinase phosphorylation but also MMP-2 activity (Li, Pan, et al., 2014), a mechanism that may involve interference with Zn2 + binding at the MMP catalytic active site. Zn2 + chelators deprive MMPs from the Zn2 + ion
Role of MMPs in Vascular Biology
MMPs play a role in many biological processes such as tissue remodeling and growth as well as tissue defense mechanisms and immune response. Increased expression of MMPs has been detected during different stages of mammalian development, from embryonic implantation to the morphogenesis of different tissues and organs including lung, bone, and blood vessels (Harvey et al., 1995, Page-McCaw et al., 2007, Vu and Werb, 2000). MMPs participate in vascular tissue remodeling, cell growth,
Role of MMPS in Vascular Pathology
Altered MMP expression/activity and MMP/TIMP imbalance could cause unrestrained tissue remodeling and multiple pathological conditions including autoimmune and inflammatory disorders, osteoarthritis, and cancer. MMPs play key roles in the spread of viral infection, inflammation, and remodeling of the respiratory airways and tissue fibrosis (Hirakawa et al., 2013). MMPs may also participate in cancer development, progression, invasiveness, and dissemination by promoting a protumorigenic
Conclusion
MMPs are important regulators of the vascular ECM and other signaling pathways in the vasculature. MMPs are involved in many biological and vascular processes and could be important biomarkers for cardiovascular disease. One hurdle to understanding the role of specific MMPs in vascular pathology is that studies often examine few MMPs or TIMPs, and it is important to not generalize the findings to other MMPs and TIMPs. Because tissue remodeling is a dynamic process, an increase in one MMP in a
Conflict of Interest
None.
Acknowledgments
This work was supported by grants from National Heart, Lung, and Blood Institute (HL-65998, HL-111775). Dr. X. Wang was a visiting scholar from the Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
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