Inhibition of Matrix Metalloproteinases (MMPs) as a Potential Strategy to Ameliorate Hypertension-Induced Cardiovascular Alterations

Michele      M. Castro; Jose      E. Tanus-Santos

doi:10.2174/1389450111314030005

Abstract

A group of proteases, the matrix metalloproteinases (MMPs) are well known for their capacity to degrade extracellular matrix (ECM) proteins. Particularly MMP-2 and MMP-9 contribute to the degradation and reorganization of the ECM components and are involved in the pathophysiology of cardiovascular remodeling. Imbalanced MMP activity promotes vascular smooth muscle cells and migration and proliferation and endothelial dysfunction, thus resulting in increased cardiovascular stiffness and hypertrophy. Furthermore, MMP-2 cleaves non-ECM protein substrates including cellular receptors and intracellular proteins, thus causing cardiac and vascular dysfunction. It is now becoming clear that increased MMP activity promotes long-lasting cardiovascular structural and functional alterations in both experimental and clinical hypertension, and this alteration may contribute to sustained hypertension and its complications. Other pathogenic mechanisms including activation of the renin-angiotensin-aldosterone system and oxidative stress activate and upregulate MMPs. Therefore, MMP inhibition may prevent the deleterious consequences of hypertension to the cardiovascular system. This review article will focus on growing evidence supporting the relevance of MMPs in hypertension and the effects of MMP inhibitors. Particularly, the effects of doxycycline used as a non selective MMP inhibitor in experimental and clinical studies will be discussed.

Keywords: Cardiovascular remodeling, doxycycline, hypertension, matrix metalloproteinases, oxidative stress, reninangiotensin-aldosterone system, Arterial hypertension, tissue inhibitors of metalloproteinases (TIMPs), VSMCs and extracellular matrix