Abstract
Hypertension is a major risk factor for cardiovascular disease. Thus, prevention of hypertension and consequent organ damage is important for reducing its incidence. In the present study, we examined the involvement of tissue inhibitor of metalloproteinase-3 (Timp-3) in Nω-nitro-L-arginine methyl ester (L-NAME)−induced hypertension and accompanying vascular remodeling in mice. L-NAME was orally administered to wild-type (WT) and Timp-3 knockout (KO) mice for 6 weeks, blood pressure was monitored, and histological changes in myocardial arteries were examined. After L-NAME administration, blood pressure was lower in Timp-3 KO mice than in WT mice. The coronary arteries of WT and Timp-3 KO mice were similar after L-NAME treatment and showed no differences compared to untreated control mice. However, cardiac microvessels differed histologically between WT and Timp-3 KO mice. Vascular walls were less thickened in Timp-3 KO than in WT mice, and fibrotic changes were significantly reduced in Timp-3 KO mice. Moreover, the L-NAME–induced production of reactive oxygen species in cardiac microvessels was lower in Timp-3 KO than in WT mice. These results indicate that Timp-3 plays an important role in L-NAME–induced hypertension and myocardial vascular remodeling. Our findings suggest that Timp-3 may be a novel therapeutic target for the treatment of hypertension and consequent organ damage.
Similar content being viewed by others
Article PDF
References
Roberts WC : The hypertensive diseases. Evidence that systemic hypertension is a greater risk factor to the development of other cardiovascular diseases than previously suspected. Am J Med 1975; 59: 523–532.
Hollander W : Role of hypertension in atherosclerosis and cardiovascular disease. Am J Cardiol 1976; 38: 786–800.
Wang JG, Staessen JA, Franklin SS, Fagard R, Gueyffier F : Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 2005; 45: 907–913.
Diamond JA, Phillips RA : Hypertensive heart disease. Hypertens Res 2005; 28: 191–202.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G : Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987; 84: 9265–9269.
Ohashi Y, Kawashima S, Hirata K, et al: Hypotension and reduced nitric oxide–elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 1998; 102: 2061–2071.
Shesely EG, Maeda N, Kim HS, et al: Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 1996; 93: 13176–13181.
Huang PL, Huang Z, Mashimo H, et al: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377: 239–242.
Hyndman ME, Parsons HG, Verma S, et al: The T-786→C mutation in endothelial nitric oxide synthase is associated with hypertension. Hypertension 2002; 39: 919–922.
Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R : Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 1992; 20: 298–303.
Baylis C, Mitruka B, Deng A : Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992; 90: 278–281.
Luvara G, Pueyo ME, Philippe M, et al: Chronic blockade of NO synthase activity induces a proinflammatory phenotype in the arterial wall: prevention by angiotensin II antagonism. Arterioscler Thromb Vasc Biol 1998; 18: 1408–1416.
Numaguchi K, Egashira K, Takemoto M, et al: Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension 1995; 26: 957–962.
Suda O, Tsutsui M, Morishita T, et al: Long-term treatment with Nω-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase–deficient mice. Circulation 2002; 106: 1729–1735.
Pechanova O, Dobesova Z, Cejka J, Kunes J, Zicha J : Vasoactive systems in L-NAME hypertension: the role of inducible nitric oxide synthase. J Hypertens 2004; 22: 167–173.
Kanematsu Y, Tsuchiya K, Ohnishi H, et al: Effects of angiotensin II type 1 receptor blockade on the systemic blood nitric oxide dynamics in Nω-nitro-L-arginine methyl ester–treated rats. Hypertens Res 2006; 29: 369–374.
Nagase H, Woessner JF Jr : Matrix metalloproteinases. J Biol Chem 1999; 274: 21491–21494.
Brew K, Dinakarpandian D, Nagase H : Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000; 1477: 267–283.
Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR : Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix–associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994; 269: 9352–9360.
Yu WH, Yu S, Meng Q, Brew K, Woessner JF Jr : TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J Biol Chem 2000; 275: 31226–31232.
Amour A, Slocombe PM, Webster A, et al: TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 1998; 435: 39–44.
Smookler DS, Mohammed FF, Kassiri Z, Duncan GS, Mak TW, Khokha R : Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation. J Immunol 2006; 176: 721–725.
Smith MR, Kung H, Durum SK, Colburn NH, Sun Y : TIMP-3 induces cell death by stabilizing TNF-alpha receptors on the surface of human colon carcinoma cells. Cytokine 1997; 9: 770–780.
Mannello F, Gazzanelli G : Tissue inhibitors of metalloproteinases and programmed cell death: conundrums, controversies and potential implications. Apoptosis 2001; 6: 479–482.
Qi JH, Ebrahem Q, Moore N, et al: A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407–415.
Fedak PW, Smookler DS, Kassiri Z, et al: TIMP-3 deficiency leads to dilated cardiomyopathy. Circulation 2004; 110: 2401–2409.
Leco KJ, Waterhouse P, Sanchez OH, et al: Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J Clin Invest 2001; 108: 817–829.
Kawamoto H, Yasuda O, Suzuki T, et al: Tissue inhibitor of metalloproteinase-3 plays important roles in the kidney following unilateral ureteral obstruction. Hypertens Res 2006; 29: 285–294.
Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U : Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet 1994; 8: 352–356.
Yeow KM, Kishnani NS, Hutton M, Hawkes SP, Murphy G, Edwards DR : Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix. Matrix Biol 2002; 21: 75–88.
Soboleva G, Geis B, Schrewe H, Weber BH : Sorsby fundus dystrophy mutation Timp3 (S156C) affects the morphological and biochemical phenotype but not metalloproteinase homeostasis. J Cell Physiol 2003; 197: 149–156.
Fabunmi RP, Sukhova GK, Sugiyama S, Libby P : Expression of tissue inhibitor of metalloproteinases-3 in human atheroma and regulation in lesion-associated cells: a potential protective mechanism in plaque stability. Circ Res 1998; 83: 270–278.
Johnson TW, Wu YX, Herdeg C, et al: Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries. Arterioscler Thromb Vasc Biol 2005; 25: 754–759.
Zhu XY, Daghini E, Chade AR, et al: Role of oxidative stress in remodeling of the myocardial microcirculation in hypertension. Arterioscler Thromb Vasc Biol 2006; 26: 1746–1752.
Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE : Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation 2001; 104: 839–844.
Carmeliet P, Moons L, Lijnen R, et al: Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 1997; 17: 439–444.
Davis GE, Pintar Allen KA, Salazar R, Maxwell SA : Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell–mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J Cell Sci 2001; 114: 917–930.
Rauchova H, Pechanova O, Kunes J, Vokurkova M, Dobesova Z, Zicha J : Chronic N-acetylcysteine administration prevents development of hypertension in Nω-nitro-L-arginine methyl ester–treated rats: the role of reactive oxygen species. Hypertens Res 2005; 28: 475–482.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Higuchi, M., Yasuda, O., Kawamoto, H. et al. Tissue Inhibitor of Metalloproteinase-3 Deficiency Inhibits Blood Pressure Elevation and Myocardial Microvascular Remodeling Induced by Chronic Administration of Nω-Nitro-L-Arginine Methyl Ester in Mice. Hypertens Res 30, 563–571 (2007). https://doi.org/10.1291/hypres.30.563
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1291/hypres.30.563
Keywords
This article is cited by
-
Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension
Journal of Thrombosis and Thrombolysis (2021)
-
Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury
Angiogenesis (2015)
-
Timp-3 deficiency impairs cognitive function in mice
Laboratory Investigation (2009)
