Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-1 Inhibits Vascular Smooth Muscle Cell Functions In Vitro and In Vivo

Forough, Reza; Koyama, Noriyuki; Hasenstab, David; Lea, Holly; Clowes, Monika M.; Nikkari, Seppo T.; Clowes, Alexander W.

doi:10.1161/01.res.79.4.812

Cited by 181 publications

(121 citation statements)

References 54 publications

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“…Increased expression of both Ang II and endothelin-1 could be generated by RVCH in keeping with the properties of mast cell chymases. In addition, chymases can activate MMPs, which could facilitate SMC proliferation (35,36). Furthermore, cells stably transfected with RVCH have elevated collagen production (unpublished data).…”

Section: Discussionmentioning

confidence: 94%

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Gros²,

You³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is up-regulated in SMC from spontaneously hypertensive vs. normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC, with the use of the tetracyclinecontrolled transactivator (tTA). We confirmed conditional expression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure (mmHg), measured by carotid artery cannulation at 10 -12 weeks of age, was higher in tTA؉͞RVCH؉ mice than in nonbinary transgenic littermates (136 ؎ 4 vs. 109 ؎ 3) (P < 0.05), as were the diastolic and mean pressures. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries from tTA؉͞RVCH؉ mice vs. littermates (0.82 ؎ 0.1 vs. 0.42 ؎ 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunoreactivity, with the use of an antibody to the proliferating cell nuclear antigen. These structural changes were prevented by doxycycline. Perfusion myography of mesenteric arteries from tTA؉͞RVCH؉ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation when compared with littermate controls or with the doxycyline-treated group. Our studies suggest that up-regulation of this vascular chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.smooth muscle cells C hymases are serine proteinases that were thought to be produced exclusively by mast cells in blood vessels and the myocardium. These enzymes generate angiotensin (Ang) II in large and resistance vessels (1-3) and in the heart (4) and also can convert big-endothelin-1 to endothelin-1 in vitro (5) and inactivate the vasodilator bradykinin (6). That chymase-dependent Ang II formation can occur in the intact animal is evident from studies in the baboon, where it was shown that Ang-converting enzyme inhibitors could not prevent the hemodynamic response to [Pro11, Da1a12]Ang I, which produces Ang II upon incubation with chymase (7). In addition to blood pressure regulation, both Ang II and endothelin-1 are involved in the stimulation of vascular smooth muscle cell (SMC) growth and proliferation, vascular remodeling, and cardiac hypertrophy (8, 9). Chymases also can influence structural remodeling through their ability to degrade extracellular matrix proteins, including fibronectin and collagen type IV, possibly through activation of matrix metalloproteinases (MMPs) (MMP-1, MMP-3, and MMP-9) (10-12). Chymases also stimulate collagen fibirillogenesis by cleavage of type I procollagen (13).Several studies have provided compelling data to suggest that chymases could play a central role in cardiovascular di...

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Section: Discussionmentioning

confidence: 94%

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Gros²,

You³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Because TIMP-1 has been shown to inhibit SMCs proliferation 14 and TIMP-2 shows significant homology to erythroid growth factors and has been previously demonstrated to stimulate proliferation of some cell types, 22 we examined the effect of AdCMV.hTIMP-2 infection on the proliferation of cultured SMCs isolated from the neointima of ballooninjured rat carotid arteries. Figure 4 shows that there was no …”

Section: Effects Of Adcmvhtimp-2 On Cultured Smc Functionmentioning

confidence: 99%

“…5,13,14 Given the particular importance of MMP-2 to vessel injury and the fact that a unique association occurs between MMP-2 and TIMP-2, 15 we constructed a replication-deficient adenovirus encoding human TIMP-2 to infect cultured SMCs as well as SMCs in vivo and assess the effects of its expression on SMC function in cell culture and neointimal development after balloon withdrawal injury.…”

mentioning

confidence: 99%

Adenovirus-Mediated Gene Transfer of the Human Tissue Inhibitor of Metalloproteinase-2 Blocks Vascular Smooth Muscle Cell Invasiveness In Vitro and Modulates Neointimal Development In Vivo

et al. 1998

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Background-Endovascular injury induced by balloon withdrawal leads to the increased activation of matrix metalloproteinases (MMPs) in the vascular wall, allowing smooth muscle cells (SMCs) to digest the surrounding extracellular matrix (ECM) and migrate from the media into the intima. The objective of this study was to examine the effects of a replication-deficient adenovirus carrying the cDNA for human tissue inhibitor of metalloproteinase-2 (AdCMV.hTIMP-2) on SMC function in vitro and neointimal development in the injured rat carotid artery. Methods and Results-Infection of cultured rat aortic SMCs at a multiplicity of infection of 100 with AdCMV.hTIMP-2 resulted in high-level expression of hTIMP-2 mRNA and protein secretion into the medium. Conditioned media (CM) from AdCMV.hTIMP-2-infected but not control virus (AdCMV.null or AdCMV.␤gal)-infected SMCs inhibited MMP-2 activity on gelatin zymograms as well as the chemoattractant-directed migration of SMCs across reconstituted basement membrane proteins in the Boyden chamber assay. In contrast, AdCMV.hTIMP-2 CM had no effect on chemoattractant-directed migration of SMCs occurring in the absence of an ECM barrier or on the proliferation of cultured neointimal SMCs. Delivery of AdCMV.hTIMP-2 (2.5ϫ10 9 pfu) to the carotid artery wall at the time of balloon withdrawal injury inhibited SMC migration into the intima by 36% (PϽ0.05) at 4 days and neointimal area by 53% (PϽ0.01) at 8 days and by 12% (PϭNS) at 21 days after injury. AdCMV.hTIMP-2 had no effect on medial area. Conclusions-Adenovirus-mediated hTIMP-2 gene transfer inhibits SMC invasiveness in vitro and in vivo and delays neointimal development after carotid injury. (Circulation. 1998;98:2195-2201.)

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“…This possibility is further supported by recent experiments with reseeding of SMC stably expressing TIMP-1 in the rat balloon injury model. 11 Our own previous studies have shown highly efficient transfer of the…”

Section: Introductionmentioning

confidence: 99%

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

et al. 1998

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Metalloproteinases (MMPs) are implicated in neointima for-21.8 ± 2.9 ng/mg wet weight/day (P Ͻ 0.05, n = 3). In situ mation and hence vein graft failure. Gene transfer to elevzymography revealed a marked inhibition of gelatinolytic ate local levels of tissue inhibitor of metalloproteinases activity by TIMP-2 gene transfer throughout the vein seg-(TIMPs) is therefore a potential treatment. In this study, we ments. Neointima formation and neointimal cell numbers have used lumenal application of a replication-defective were reduced 79% and 71%, respectively (P Ͻ 0.05; recombinant adenovirus to overexpress TIMP-2 and n = 8). TIMP-2 overexpression had no effect on smooth observe the effects on neointimal thickening in a well muscle cell proliferation, secretion of pro-MMP-2 or -9 and characterised human saphenous vein organ culture model.did not inhibit the processing of pro-MMP-2 to its active Increased TIMP-2 expression was localised to lumenal form. Our data indicate that TIMP-2 overexpression surface cells but nevertheless increased total functional reduces neointimal thickening, primarily by inhibiting MMP TIMP-2 secretion after 14 days culture from 4.0 ± 2.0 to activity and hence smooth muscle cell migration.

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Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-1 Inhibits Vascular Smooth Muscle Cell Functions In Vitro and In Vivo

Cited by 181 publications

References 54 publications

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Adenovirus-Mediated Gene Transfer of the Human Tissue Inhibitor of Metalloproteinase-2 Blocks Vascular Smooth Muscle Cell Invasiveness In Vitro and Modulates Neointimal Development In Vivo

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

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