Transforming Growth Factor-β2 and Connective Tissue Growth Factor in Proliferative Vitreoretinal Diseases

Kita, Takeshi; Hata, Yoshinobu; Kano, Kumiko; Matsuda, Masayoshi; Nakao, Shintaro; Noda, Yoichi; Shimokawa, Hiroaki; Ishibashi, Tatsuro

doi:10.2337/db06-0581

Cited by 107 publications

(83 citation statements)

References 48 publications

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“…This is plausible when considering that TAK1-(JNK1/2)/P38 serves as an important pathway in the fibrotic response by promoting production of profibrotic factors, such as connective tissue growth factor. 49,50 Here, we observed that cardiomyocyte-specific USP4 overexpression drastically inhibited TAK1-(JNK1/2)/ P38 signaling activation and connective tissue growth factor production in hypertrophic myocardium. Connective tissue growth factor is one of the most important profibrotic growth factors that can be transcriptionally induced by hypertrophic stimuli in myocytes and can propagate the fibrotic response as a paracrine factor.…”

Section: Discussionmentioning

confidence: 76%

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Zhao

Gao

et al. 2016

Hypertension

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Abstract-Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain-and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy. promotes ionizing radiation-induced cell apoptosis by specifically reducing p53 expression. 13 Of note, USP4 is a putative proto-oncogene, which promotes epithelial to mesenchymal transition and breast cancer cell migration. 18 Interestingly, mounting evidence supports pivotal roles of proto-oncogenes in modulating cardiac hypertrophy, 19,20 indicating a potential involvement of USP4 in cardiac hypertrophy. We therefore posited that USP4, a DUB prominently expressed in the heart, might be a potential signaling regulator implicated in cardiac hypertrophy.In this study, we observed reduced levels of USP4 in hearts from patients with dilated cardiomyopathy and in animal models of cardiac hypertrophy induced by pressure overload. By subjecting USP4 knockout mice and transgenic mice with cardiac-specific USP4 overexpression to aortic banding (AB), we observed that USP4 deficiency aggravated hypertrophic growth and cardiac dysfunction. Conversely, restoration of USP4 level remarkably protected the heart against pathological hypertrophy. Mechanistically, the beneficial effect of USP4 was largely dependent on the blockade of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling. Materials and MethodsThe animal protocol was approved by the Instit...

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Section: Discussionmentioning

confidence: 76%

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Zhao

Gao

et al. 2016

Hypertension

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“…Various cytokines, such as TGF-␤, connective tissue growth factor, interleukin-6, and platelet-derived growth factor (PDGF), are overexpressed in the vitreous and membranes associated with PDR and PVR, and they contribute to the pathogenesis of these diseases (15,(37)(38)(39)(40). Among these cytokines, TGF-␤2 induces the transformation of retinal pigment epithelial cells or hyalocytes to myofibroblastic cells (18,41) and plays a key role in the formation and contraction of proliferative membranes.…”

Section: Discussionmentioning

confidence: 99%

Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins

et al. 2008

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OBJECTIVE-Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.RESEARCH DESIGN AND METHODS-Human vitreous concentrations of transforming growth factor-␤2 (TGF-␤2) were measured by enzyme-linked immunosorbent assay. TGF-␤2-and vitreous-dependent phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase pathway, and collagen gel contraction simulating cicatrical contraction were analyzed using cultured hyalocytes. Inhibitory effects of simvastatin on cicatrical contraction were assessed both in vitro and in vivo.RESULTS-Human vitreous concentrations of TGF-␤2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-␤2-dependent MLC phosphorylation and gel contraction in a dose-and time-dependent manner and was capable of inhibiting translocation of Rho protein to the plasma membrane in the presence of TGF-␤2. Vitreous samples from patients with PVD enhanced MLC phosphorylation and gel contraction, whereas simvastatin almost completely inhibited these phenomena. Finally, intravitreal injection of simvastatin dose-dependently prevented the progression of diseased states in an in vivo model of PVR.CONCLUSIONS-Statins might have therapeutic potential in the prevention of PVDs.

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“…11 TGF-b is induced in the vitreous in proliferative diabetic retinopathy and proliferative vitreoretinopathy. [12][13][14] Matrix metalloproteinases (MMPs) are calcium-or zinc-dependent extracellular proteolytic enzymes that have a role in degrading and remodelling of extracellular matrix in various physiological and pathological conditions including ischemic vitreoretinal eye diseases. 15,16 Especially, MMP-2 and -9 are linked to a variety of EC functions, including proliferation, differentiation, and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

Tuuminen

Loukovaara

2014

Eye

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Purpose Vascular endothelial growth factor is a leading target to reduce macular oedema and improve visual acuity in patients with retinal vein occlusion (RVO), whereas the role of vascular destabilizing and fibroproliferative transforming growth factor (TGF)-b1 and matrix metalloproteinases (MMP)-2 and -9 in pathological manifestations of RVO is anticipated but less studied. Methods Undiluted vitreous samples were collected from three central RVO and one branch RVO eyes, all with neovascularization and fibrosis-related sight-threatening complications of RVO. Undiluted vitreous samples of 40 eyes operated due to nonischemic condition either macular hole or pucker were used as controls. Growth factor and protease concentrations were measured by ELISA and gelatin zymography. Results Vitreous concentrations of TGF-b1 (92.0 ± 17.4 pg/ml vs 18.3 ± 27.0 pg/ml, mean ± SD; P ¼ 0.002) and MMP-9 (847.9 ± 1196.4 AU/ml vs 87.7 ± 174.0 AU/ml; P ¼ 0.010) were higher in the eyes with ischemic RVO than in the controls. Conclusions High intravitreal levels of TGF-b1 and MMP-9 are found in RVO eyes having neovascular and fibrosis manifestation. Further studies are warranted to elucidate whether targeting TGF-b1 and MMP-9 could be beneficial in patients with ischemic RVO.

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Transforming Growth Factor-β2 and Connective Tissue Growth Factor in Proliferative Vitreoretinal Diseases

Cited by 107 publications

References 48 publications

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

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