Matrix metalloproteinases: targets for doxycycline to prevent the vascular alterations of hypertension

Abstract

Hypertension is associated with well known structural and functional alterations in both resistance and conduit arteries, which may be the result from long-lasting high blood pressure and may also be the cause of maintained hypertension and its complications. Therefore, in addition to lowering blood pressure, therapeutic strategies targeting the structural and functional modifications found in hypertensive patients may prevent the cardiovascular events and decrease the death rates associated with hypertension. Mounting evidence indicates that many vascular alterations associated with sustained hypertension are due to imbalanced matrix metalloproteinases (MMPs), a family of zinc-endopeptidases that degrade not only proteins of extracellular matrix (ECM) but several other substrates. Recent observations showed that abnormal MMP activity is a feature of the pathogenesis of hypertension and other diseases, thus justifying the development of drugs aiming at MMP downregulation. This review focuses on the extracellular actions of MMPs in hypertension-induced chronic vascular alterations. We then discuss the effects of MMP inhibitors, especially doxycycline, on the vascular changes associated with hypertension. There is now strong evidence that MMP inhibition with doxycycline (and maybe other MMP inhibitors) may attenuate the functional and structural alterations associated with hypertension, including increases in arterial stiffness. These beneficial effects may be, at least in part, independent of their antihypertensive effects.