New Insights into the Role of Basement Membrane-Derived Matricryptins in the Heart

Abstract

The extracellular matrix (ECM), which contributes to structural homeostasis as well as to the regulation of cellular function, is enzymatically cleaved by proteases, such as matrix metalloproteinases and cathepsins, in the normal and diseased heart. During the past two decades, matricryptins have been defined as fragments of ECM with a biologically active cryptic site, namely the 'matricryptic site,' and their biological activities have been initially identified and clarified, including anti-angiogenic and anti-tumor effects. Thus, matricryptins are expected to be novel anti-tumor drugs, and thus widely investigated. Although there are a smaller number of studies on the expression and function of matricryptins in fields other than cancer research, some matricryptins have been recently clarified to have biological functions beyond an anti-angiogenic effect in heart. This review particularly focuses on the expression and function of basement membrane-derived matricryptins, including arresten, canstatin, tumstatin, endostatin and endorepellin, during cardiac diseases leading to heart failure such as cardiac hypertrophy and myocardial infarction.

The Non-Fibrillar Side of Fibrosis: Contribution of the Basement Membrane, Proteoglycans, and Glycoproteins to Myocardial Fibrosis

“…Cleavage product of collagen IVα2 by MT1-MMP and MT2-MMP [166]. Expression is decreased 1-day post-MI [174].…”

“…This term is only used in referring to biologically active fragments that contain a cryptic domain that is not normally exposed in the intact molecule (Table 3). Matricryptins such as endostatin and tumstatin are naturally occurring fragments of basement membrane (non-fibrillar) collagens XVIII and IV, respectively, and have been reported to possess biological functions such as anti-angiogenic effects, and are associated with various diseases including cardiovascular diseases [165,166]. However, the function of endostatin remains controversial.…”

“…Collagen IV, a non-fibrillar collagen and a predominant protein in myocardial basement membrane, has been identified to contain several matricryptins that are released through the proteolytic function of MMPs. These matricryptins include arresten (α1 chain, by MT1-MMP and MT2-MMP), canstatin (α2 chain, by MT1-MMP and MT2-MMP), tumstatin (α3 chain, by MMP9), tetrastatin (α4 chain), pentastatin (α5 chain) and hexastatin (α6 chain) [166]. A few matricryptins have been reported to impact fibroblast function and therefore are implicated in myocardial fibrosis.…”

“…Cleavage product of collagen IVα3 by MMP9 [166]. Expression is increased after cardiac pressure overload [173].…”

N-Terminomics/TAILS Profiling of Proteases and Their Substrates in Ulcerative Colitis

“…Previous studies have focused on the degradative properties of inflammatory proteases due to their significantly elevated levels in ulcerative colitis patients; however, our data suggest inflammatory proteases may be directly regulating cellular processes in a nondestructive, targeted manner via the creation of unique peptide signatures, creating new functional reactomes and protease web interactions. Indeed, while the role of bioactive peptides from extracellular matrix proteins and their contributions to tissue repair and homeostasis have been well established in skin and cardiac studies, − few studies have examined the larger contributions of small peptide molecules and proteolytic regulation of tissue repair and homeostasis in other organ system. At least one study has identified significant basement matrix remodelling in ulcerative colitis as a result of altered proteolytic activity, which is consistent with our results, and degradation of therapeutic biologic antibodies by host proteases has been shown to be a potential cause for nonresponse in UC patients, although the implications of epithelial remodelling by proteases remains to be better characterized.…”