Chymase and Matrix Metalloproteinase

3 Hypertens Res Vol.30 (2007) No.1 p.3-4 Editorial Comment Chymase and Matrix Metalloproteinase Hidenori URATA1) (Hypertens Res 2007; 30: 3–4) Key Words: chymase, matrix metalloproteinase, neointimal proliferation, chymase inhibitor Matrix metalloproteinases (MMPs) are a family of zinc-binding proteases that are capable of degrading extracellular matrix (ECM) during tissue remodeling, including organogenesis, wound healing (1), tumor invasion and angiogenesis (2). MMP-2 (collagenase A) is the major ECM-degrading protease and specifically degrades the basement membrane. Regarding vascular remodeling after balloon injury, MMP-2 is expressed abundantly in restenotic lesions, and the inhibition of MMP-2 by thapsigargin reduces neointima formation (3). In nonhuman primates, MMPs increase with age, and this increase has been positively correlated with the intimal thickening of the carotid artery (4). Recently, it has been reported that chymase activates several inactive precursors of MMPs (5–7). This finding revealed a new aspect of the function of chymase, in addition to its action as a potent angiotensin II (Ang II)–forming enzyme. It has been reported that chymase produces Ang II (8), which may play a crucial role in coronary artery restenosis. Ang II subtype 1 receptor blocker (ARB) has been proven effective for preventing restenosis after percutaneous coronary angioplasty, but not angiotensin I converting enzyme inhibitor (9, 10). After balloon injury in dog arteries, vascular chymase activity significantly increased and a chymase inhibitor and an ARB were effective in preventing vascular proliferation (11). These studies suggest that chymase-dependent Ang II formation is also harmful in that it promotes the development of vascular hypertrophy in the injured arteries. In this issue of Hypertension Research, Kishi et al. (12) report that chymase is involved in the neointimal proliferation after balloon injury in the dog carotid artery. The oral administration of NK3201, a chymase inhibitor, prevented neointimal formation and significantly suppressed both active MMP-2 and chymase activities 2 weeks after balloon injury. These results suggest that chymase inhibitors can prevent the development of intimal hyperplasia via the inhibition of MMP-2 activation in the balloon-injured artery. Disappointingly, the use of drug-eluting stents has not resulted in a lower rate of adverse events compared to coronary bypass operation, especially in patients with complex lesions or multiple risk factors (13). It has been reported that increased arterial chymase activity is associated with development of atherosclerotic lesions in humans (14), and orally active chymase inhibitor has been shown to reverse this process in high cholesterol–loaded hamsters (15). These data further imply that the clinical application of chymase inhibitor is warranted to prevent atherosclerosis or restenosis after coronary intervention. References 1. 2. 3. 4. 5. Moses MA, Marikovsky M, Harper JW, et al: Temporal study of the activity of matrix metalloproteinases and their endogenous inhibitors during wound healing. J Cell Biochem 1996; 60: 379–386. Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980; 284: 67–68. George SJ, Johnson JL, Angelini GD, Jeremy JY: Shortterm exposure to thapsigargin inhibits neointima formation in human saphenous vein. Arterioscler Thromb Vasc Biol 1997; 17: 2500–2506. Wang M, Takagi G, Asai K, et al: Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 2003; 41: 1308–1316. Suzuki K, Lees M, Newlands GF, Nagase H, Woolley DE: Activation of precursors for matrix metalloproteinases 1 From the 1)Department of Cardiovascular Diseases, Fukuoka University Chikushi Hospital, Chikushino, Japan. Address for Reprints: Hidenori Urata, M.D., Department of Cardiovascular Diseases, Fukuoka University Chikushi Hospital, 1–1–1 Zokumyoin, Chikushino 818–8502, Japan. E-mail: Received December 18, 2006. 4 Hypertens Res Vol. 30, No. 1 (2007) (interstitial collagenase) and 3 (stromelysin) by rat mast-cell proteinases I and II. Biochem J 1995; 305: 301–306. 6. Fang KC, Raymond WW, Blount JL, Caughey GH: Dog mast cell alpha-chymase activates progelatinase B by cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of the catalytic domain. J Biol Chem 1997; 272: 25628–25635. 7. Tchougounova E, Lundequist A, Fajardo I, Winberg JO, Abrink M, Pejler G: A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. 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