Pharmacological Research 64 (2011) 551–560 Contents lists available at ScienceDirect Pharmacological Research jo ur n al hom epage: www.elsevier.com/locate/yphrs Review Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases Michele M. Castro, Arulmozhi D. Kandasamy, Nermeen Youssef, Richard Schulz ∗ Departments of Pharmacology & Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada a r t i c l e i n f o Keywords: Tetracyclines Matrix metalloproteinase Doxycycline Ischemia/reperfusion injury Inflammatory heart disease Septic shock a b s t r a c t Matrix metalloproteinases (MMPs) are a family of proteases best known for their capacity to proteolyse several proteins of the extracellular matrix. Their increased activity contributes to the pathogenesis of several cardiovascular diseases. MMP-2 in particular is now considered to be also an important intracel- lular protease which has the ability to proteolyse specific intracellular proteins in cardiac muscle cells and thus reduce contractile function. Accordingly, inhibition of MMPs is a growing therapeutic aim in the treatment or prevention of various cardiovascular diseases. Tetracyclines, especially doxycycline, have been frequently used as important MMP inhibitors since they inhibit MMP activity independently of their antimicrobial properties. In this review we will focus on the intracellular actions of MMPs in some cardio- vascular diseases including ischemia and reperfusion (I/R) injury, inflammatory heart diseases and septic shock; and explain how tetracyclines, as MMP inhibitors, have therapeutic actions to treat such diseases. We will also briefly discuss how MMPs can be intracellularly regulated and activated by oxidative stress, thus cleaving several important proteins inside cells. In addition to their potential therapeutic effects, MMP inhibitors may also be useful tools to understand the biological consequences of MMP activity and its respective extra- and intracellular effects. © 2011 Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551 2. MMP structure, activation and regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 2.1. Regulation of MMP-2 by glutathiolation, phosphorylation and TIMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 2.1.1. Glutathiolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 2.1.2. Phosphorylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 2.1.3. TIMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 3. Pharmacological inhibitors of MMPs: focus on the tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 4. Physiological role of MMPs in the development of heart and vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 5. MMP inhibition in myocardial I/R injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 5.1. Discovery of intracellular MMP activity in myocardial I/R injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 5.2. Clinical studies of I/R injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554 6. MMP inhibition in inflammatory heart diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 7. MMPs in the regulation of vascular tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 8. MMP inhibition in sepsis: focus on vascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 Abbreviations: CMTs, Chemically modified tetracyclines; I/R, Ischemia–reperfusion; MMPs, Matrix metalloproteinases; ONOO - , Peroxynitrite; TIMPs, Tissue inhibitors of metalloproteinases. ∗ Corresponding author at: Cardiovascular Research Centre, 4-62 Heritage Medi- cal Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. Tel.: +1 780 492 6581; fax: +1 780 492 9753. E-mail address: richard.schulz@ualberta.ca (R. Schulz). 1. Introduction Matrix metalloproteinases (MMPs) are a family of zinc- dependent endopeptidases, first discovered in 1962 by Gross and Lapiere, as a collagen-degrading enzyme activity responsible for tadpole tail morphogenesis [1]. Since then, especially due to their 1043-6618/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2011.05.005