Matrix metalloproteinase-2 (MMP-2), previously named 72 kDa type IV collagenase or gelatinase A, belongs to the MMP family of calcium and zinc-dependent endopeptidases. MMPs were originally considered to be secreted proteases which play a major role in degrading extracellular matrix (ECM) proteins. In addition to its canonical role in ECM remodelling, MMP-2 has many nonmatrix extracellular and intracellular substrates (Schulz 2007; Spinale 2007). The list of identified MMP-2 substrates continues to grow and includes sarcomeric proteins, membrane receptors, cytokines, and growth factors. Consequently, MMP-2 regulates a vast range of physiological processes, from angiogenesis to wound healing and tissue remodeling. However, aberrant activation of MMP-2 contributes to many pathophysiological conditions, including inflammation, cancer metastasis, and cardiovascular diseases, making it a target of interest for therapeutic...
We thank Dawne Colwell for her help with graphics. Research in the Schulz lab is supported by the Canadian Institutes of Health Research (FDN 143299) and the Heart and Stroke Foundation of Canada. Brandon Chan received a WCHRI graduate studentship award which is funded by the support of the Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute.
- Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH. A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimers. Biochem J. 2003;369:485–96. https://doi.org/10.1042/BJ20020707.CrossRefPubMedPubMedCentralGoogle Scholar
- Buchholz B, Perez V, Siachoque N, Miksztowicz V, Berg G, Rodríguez M, et al. Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2014;307:H88–96. https://doi.org/10.1152/ajpheart.00242.2013.-Dystrophin.CrossRefPubMedGoogle Scholar
- Cerisano G, Buonamici P, Valenti R, Sciagrà R, Raspanti S, Santini A, et al. Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial. Eur Heart J. 2014;35:184–91. https://doi.org/10.1093/eurheartj/eht420.CrossRefPubMedGoogle Scholar
- Dean RA, Butler GS, Hamma-Kourbali Y, Delbe J, Brigstock DR, Courty J, et al. Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis. Mol Cell Biol. 2007;27:8454–65. https://doi.org/10.1128/MCB.00821-07.CrossRefPubMedPubMedCentralGoogle Scholar
- Hughes BG, Fan X, Cho WJ, Schulz R. MMP-2 is localized to the mitochondria-associated membrane of the heart. Am J Physiol Heart Circ Physiol. 2014;306:H764–H70. https://doi.org/10.1152/ajpheart.00909.2013.-Matrix.CrossRefPubMedGoogle Scholar
- Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, et al. A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One. 2012;7:e34177. https://doi.org/10.1371/journal.pone.0034177.CrossRefPubMedPubMedCentralGoogle Scholar
- Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol. 2007;47:211–42. https://doi.org/10.1146/annurev.pharmtox.47.120505.105230.CrossRefPubMedGoogle Scholar
- Spinale F. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res. 2002;90:520–30. https://doi.org/10.1161/01.res.0000013290.12884.a3.CrossRefPubMedGoogle Scholar
- Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J. Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation. 2003;108:1487–92. https://doi.org/10.1161/01.CIR.0000089090.05757.34.CrossRefPubMedGoogle Scholar
- Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39. https://doi.org/10.1161/01.RES.0000070112.80711.3D.CrossRefPubMedGoogle Scholar
- Wang W, Schulze CJ, Suarez-Pinzon W, Dyck J, Sawicki S, Schulz R. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation. 2002;106:1543–9. https://doi.org/10.1161/01.cir.0000028818.33488.7b.CrossRefPubMedGoogle Scholar