Inhibition of Matrix Metalloproteinase and Hypertension

477 Hypertens Res Vol.30 (2007) No.6 p.477-478 Editorial Comment Inhibition of Matrix Metalloproteinase and Hypertension Takafumi OKURA1) and Jitsuo HIGAKI1) (Hypertens Res 2007; 30: 477–478) Key Words: matrix metalloproteinases (MMPs), natural tissue inhibitors of MMP (TIMP)-3, hypertension, Nωnitro-L-arginine methyl ester, a disintegrin and metalloproteinase (ADAM)17 Matrix metalloproteinases (MMPs) are zinc-endopeptidases involved in numerous physiological and pathological processes. MMPs play roles in tissue growth, angiogenesis, cell migration, inflammation, wound healing, cardiovascular disease, cancer and metastasis (1). The natural tissue inhibitors of MMPs (TIMPs) are a family of inhibitors capable of regulating MMP activity (2). The four members have many similarities and overlapping specificities, but their biological properties and local expression patterns exhibit distinctive features. TIMP-3 is the only TIMP that binds to the extracellular matrix by its interaction with chondroitin sulfate and heparan sulfate (3). Furthermore, TIMP-3 contains an amino acid sequence required to inhibit a disintegrin and metalloproteinase (ADAM)17, also called tumor necrosis factor (TNF)-α converting enzyme (TACE) (4). ADAM17 is responsible for the release of several transmembrane proteins, including neuregulins 1 and 2, fractalkine, and TNF-α (5). In this issue of Hypertension Research, Higuchi et al. report that TIMP-3 deficiency inhibited blood pressure elevation and myocardial microvascular remodeling induced by chronic administration of N ω-nitro-L-arginine methyl ester (L-NAME) (6). Chronic administration of L-NAME induced hypertension and increased the wall-to-lumen ratio and perivascular fibrosis. Mice deficient in TIMP-3 gene expression showed a partial reduction in these L-NAME–induced phenomena. Furthermore, Higuchi et al. (6) showed that LNAME–induced production of reactive oxygen species (ROS) in cardiac microvessels was lower in TIMP-3 knockout mice than wild type mice. These findings constitute new evidence of a direct association between MMP-related molecules and hypertension. Numerous reports have shown the pathophysiological importance of MMPs and TIMPs in cardiovascular diseases, such as heart failure, myocardial infarction, stroke, aortic aneurysm and aortitis syndrome. However, there have been few reports examining the relationship between MMP/TIMP and hypertension. The serum concentration and roles of MMP or TIMP in hypertensive patients are controversial. Those reports that are available show conflicting results in regard to the serum concentration and roles of MMP and TIMP in hypertension. The fact that MMP/TIMP is involved in the pathophysiology of L-NAME–induced hypertension and organ damage is quite interesting. To understand why TIMP-3 deficiency influences L-NAME–induced hypertension and organ damage would be more interesting, since TIMP-3 has unique functions other than inhibition of MMPs. For example, overexpression of TIMP-3 induces apoptosis in vascular smooth muscle cells but not endothelial cells (7). This unique ability makes TIMP-3 particularly suitable as a potent inhibitor of restenosis after coronary intervention. Johnson et al. reported that stent-based delivery of TIMP-3 adenovirus inhibited neointimal formation in porcine coronary arteries (8). TIMP-3 inhibits the activity of ADAMs, including ADAM10, 12, 17, and 19. ADAM17 (TACE) can alter the availability of TNF-α by cleaving it from myeloid and T cells, allowing the shed molecules to diffuse and act on the surrounding tissue and vasculature, as well as at distant sites. Thus the regulation of ADAM17 is an important check point From the 1)Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Toon, Japan. Address for Reprints: Takafumi Okura, M.D., Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Toon 791–0295, Japan. E-mail: Received March 7, 2007. 478 Hypertens Res Vol. 30, No. 6 (2007) for the magnitude of an inflammatory response (9). ADAM17 activity might be related to the reactive oxygen species generation in TIMP-3 deficient mice. Finally, TIMP-3 deficiency or MMP activation might reduce the activation of the reninangiotensin system (RAS), which was recently reported to play a role in L-NAME–induced hypertension and organ damage by promoting oxidative stress (10). In conclusion, the paper of Higuchi et al. (6) suggests that inhibition of TIMP-3 may be a promising new strategy for the treatment of hypertension and target organ damage. 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