Dynamic Changes in Myocardial Matrix and Relevance to Disease

Li, Ai-Hsien; Liu, Peter P.; Villarreal, Francisco; Garcia, Ricardo Alexandrino

doi:10.1161/circresaha.114.302819

Cited by 111 publications

(89 citation statements)

References 144 publications

(164 reference statements)

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“…48 Results of this study surprisingly indicated that cardiomyocyte-specific overexpression of USP4 dramatically reduced interstitial and perivascular fibrosis. 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.…”

Section: Discussionmentioning

confidence: 70%

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: 70%

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

Zhao

Gao

et al. 2016

Hypertension

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“…Color images available online at www .liebertpub.com/tea However, further investigation is warranted regarding, as to which marker is best suited to reflect changes in the setting of MI, because of the complex dynamics of the myocardial ECM responses. 25 Moreover, elastin is one of the major ECM components. In the process of recovering from MI, the necrotic myocardium is replaced by collagen fibers, especially collagen type I and type III, and elasticity is lost in the scarred area.…”

Section: Discussionmentioning

confidence: 99%

A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy

Shudo

Cohen

MacArthur

et al. 2015

Tissue Engineering Part A

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There exists a substantial body of work describing cardiac support devices to mechanically support the left ventricle (LV); however, these devices lack biological effects. To remedy this, we implemented a cell sheet engineering approach utilizing chondrocytes, which in their natural environment produce a relatively elastic extracellular matrix (ECM) for a cushioning effect. Therefore, we hypothesized that a chondrocyte cell sheet applied to infarcted and borderzone myocardium will biologically enhance the ventricular ECM and increase elasticity to augment cardiac function in a model of ischemic cardiomyopathy (ICM). Primary articular cartilage chondrocytes of Wistar rats were isolated and cultured on temperature-responsive culture dishes to generate cell sheets. A rodent ICM model was created by ligating the left anterior descending coronary artery. Rats were divided into two groups: cell sheet transplantation (1.0 · 10 7 cells/dish) and no treatment. The cell sheet was placed onto the surface of the heart covering the infarct and borderzone areas. At 4 weeks following treatment, the decreased fibrotic extension and increased elastic microfiber networks in the infarct and borderzone areas correlated with this technology's potential to stimulate ECM formation. The enhanced ventricular elasticity was further confirmed by the axial stretch test, which revealed that the cell sheet tended to attenuate tensile modulus, a parameter of stiffness. This translated to increased wall thickness in the infarct area, decreased LV volume, wall stress, mass, and improvement of LV function. Thus, the chondrocyte cell sheet strengthens the ventricular biomechanical properties by inducing the formation of elastic microfiber networks in ICM, resulting in attenuated myocardial stiffness and improved myocardial function.

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“…Collagen synthesis of cardiac myofibroblasts is perceived to be important in the development of cardiac fibrosis (15,16). Therefore, the role of NRG on collagen synthesis was detected via the mRNA levels of CTGF, collagen I and collagen III.…”

Section: Nrg Treatment Inhibits Collagen Synthesis Of Cfsmentioning

confidence: 99%

Naringenin inhibits transforming growth factor‑β1‑induced cardiac fibroblast proliferation and collagen synthesis via G0/G1 arrest

Liu

Zhao

et al. 2017

Exp Ther Med

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Abstract. The Traditional Chinese Medicine naringenin (NRG) has a number of biological effects, including anti-inflammatory, anti-oxidative, anti-tumor and anti-atherosclerotic effects. However, the mechanism underlying its effects remains unclear. The aim of the present study is to investigate the role and mechanism of NRG on proliferation and collagen synthesis of cardiac fibroblasts (CFs) induced by transforming growth factor β1 (TGF-β1). Firstly, proliferation and collagen synthesis in CFs subjected to TGF-β1 was assessed subsequent to the consumption of NRG or control treatment. Additionally, the cell cycle of different groups and the roles of cyclins and cyclin-dependent kinases (CDKs) in NRG treatment of CFs were detected. In the present study, it was revealed that treatment of CFs with NRG resulted in attenuated fibroblast α-smooth muscle actin expression, deceased proliferation and collagen synthesis when compared with a TGF-β1 stimulus. Additionally, it was demonstrated that cell population of CFs treated with NRG in the S-phase became smaller whereas that of CFs in the G0/G1-phase increased when compared with the TGF-β1 group. Mechanistically, the expression of cyclin D1-CDK4/6 and cyclin E2-CDK2 were inhibited in the NRG treatment group. These results illustrated that the protective effects of NRG on proliferation and collagen synthesis of CFs were at least in part due to G0/G1 arrest. Therefore, NRG may become a novel strategy for treating cardiac fibrosis in the future.

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Dynamic Changes in Myocardial Matrix and Relevance to Disease

Cited by 111 publications

References 144 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

A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy

Naringenin inhibits transforming growth factor‑β1‑induced cardiac fibroblast proliferation and collagen synthesis via G0/G1 arrest

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