Matrix metalloproteinase in the cardiovascular remodeling of hypertension: current insights and therapeutic potential

摘要

Hypertension induces maladaptive vascular and cardiac remodeling, which are related to rearrangement of the extracellular matrix (ECM) and cell hypertrophy and migration. Matrix metalloproteinases (MMPs) are zinc-dependent proteases involved in tissue remodeling mainly by the proteolysis of ECM components. Increased MMP-2 activity is also involved in the proteolysis of important intracellular targets in cardiomyocytes and vascular smooth muscle cells (VSMC). Troponin I and calponin-1 are some of the targets of MMP-2 in cardiomyocytes and VSMC, respectively, that when degraded contribute to contractile dysfunction, cell hypertrophy or migration. MMP-2 may be activated by S-glutathiolation in vitro by peroxynitrite which frees the pro-peptide domain from the catalytic site and generates an active, 72 kDa MMP-2. Since hypertension is significant related to oxidative stress, and approximately half of newly formed MMP-2 is held inside the cell, increased peroxynitrite production may lead to the intracellular activation of MMP-2. MMP inhibitors may be a significant new opportunity to be used as adjuvants to treat hypertension as they substantially decrease maladaptive cardiovascular remodeling and then prevent the development of many other associated diseases. Antioxidants and antihypertensive drugs also contribute to decrease MMP activity and hypertrophic remodeling in hypertension. New pharmacological tools are needed to specifically decrease intracellular MMP-2 activity and thus help reduce cell migration and hypertrophy in hypertension.