Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases

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 intracellular 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 cardiovascular 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.