Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling


Matrix metalloproteinases (MMPs) and their endogenous inhibitors have been studied in the myocardium for the past 2 decades. An incomplete knowledge base and experimental design issues with inhibitors have hampered attempts at translation, but clinical interest remains high because of strong associations between MMPs and outcomes after myocardial infarction (MI) as well as mechanistic studies showing MMP involvement at multiple stages of the MI wound-healing process. This Review focuses on how our understanding of MMPs has evolved from a one-dimensional early focus on measuring MMP activity, monitoring MMP:inhibitor ratios, and evaluating one MMP–substrate pair to the current use of systems biology approaches to integrate the whole MMP repertoire of roles in the left ventricular response to MI. MMP9 is used as an example MMP to explain these concepts and to provide a template for examining MMPs as mechanistic mediators of cardiac remodelling.

Key points

  • Matrix metalloproteinases (MMPs) are not one-size-fits-all enzymes; MMPs overlap in substrate profiles, but each has a distinct role in cardiac remodelling after myocardial infarction.

  • MMP9 is the most-studied MMP in cardiac remodelling after myocardial infarction.

  • MMP roles are dictated by the substrates they process, and the best way to assess in vivo MMP activity is to show substrate cleavage.

  • The mechanisms by which MMPs interact with each other in the myocardium have not been examined beyond which MMPs compensate for the loss of one MMP and which MMPs serve as upstream activators for other MMPs.

  • This Review provides a template for examining MMPs as mechanistic mediators of cardiac remodelling.

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Fig. 1: Modifiers of MMP9 expression and activity12,28,50,63,64,65,66.
Fig. 2: Template for establishing MMP9 causality.
Fig. 3: Template for identifying and evaluating extracellular matrix fragments generated by MMP9.
Fig. 4: MMP9 roles in cardiac remodelling after myocardial infarction26,67,68,69,70,71,72,73,74.


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The author acknowledges O. J. Rivera Gonzalez and A. J. Mouton (University of Mississippi Medical Center, Jackson, MS, USA) for help with fact checking and careful proofreading of the manuscript. She acknowledges funding from the NIH under Award Numbers GM104357, GM114833, GM115428, HL051971, HL075360, and HL129823, and from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development under Award Number 5I01BX000505. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH or the Veterans Administration.

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Nature Reviews Cardiology thanks A. D. Bradshaw and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Merry L. Lindsey.

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Lindsey, M.L. Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling. Nat Rev Cardiol 15, 471–479 (2018).

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