The Roles of a Matricellular CCN Family Protein CCN5 in Cardiac Fibrosis of Heart Failure

Nano LIFE ◽  
2019 ◽  
Vol 09 (03) ◽  
pp. 1941003
Author(s):  
Jie Liu ◽  
Tao Zhuang ◽  
Xiaoli Chen ◽  
Lin Zhang ◽  
Yuzhen Zhang
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Cardiac Fibrosis ◽  
Severe Heart Failure ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Post Injury ◽  
Ccn Family ◽  
Nonstructural Components ◽  
Major Player

Cardiac fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease and a post-injury response that drives progression to heart failure. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, such as angiotensin II, TGF-[Formula: see text] and endothelin-1, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Matricellular CCN proteins spatiotemporally regulated nonstructural components of the extracellular matrix (ECM) and participated in many essential biological functions, including wound healing and fibrotic diseases. CCN5 exhibited the opposing effects of CCN2 on the development of cardiac hypertrophy and fibrosis, and overexpression of matricellular protein CCN5 in the heart by adenoviral deliver significantly improved cardiac fibrosis in severe heart failure. Future time- and cell-specific study of CCN5 effect and its domain-specific function on fibrotic development and progression will advance our understanding of cardiac fibrosis, and meanwhile provide opportunities for therapeutic intervention of heart failure.

scholarly journals Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload

Cardiology ◽  
2020 ◽  
Vol 145 (3) ◽  
pp. 187-198 ◽  
Author(s):  
Naiyereh Mohammadzadeh ◽  
Arne Olav Melleby ◽  
Sheryl Palmero ◽  
Ivar Sjaastad ◽  
Shukti Chakravarti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Linking ◽  
Myocardial Remodeling ◽  
Functional Changes ◽  
Collagen Cross Linking

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so­lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

A tangled tale of microRNA and cardiac fibrosis

2019 ◽  
Vol 133 (21) ◽  
pp. 2217-2220 ◽  
Author(s):  
Mark Chandy
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Wound Healing ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Clinical Science ◽  
Therapeutic Options ◽  
Diagnostic Modalities

Abstract Cardiac fibrosis is important for wound healing, regeneration and producing the extracellular matrix (ECM) that provides the scaffold for cells. In pathological situations, fibroblasts are activated and remodel the ECM. In volume 133, issue 17 of Clinical Science, Yang et al. discovered that the miR-214-3p/NLRC5 axis is important for fibroblast-to-myofibroblast transition (FMT) and ECM remodelling in a pressure overload model of fibrosis [Clin. Sci. (2019) 133(17), 1845–1856]. This discovery helps to explain the complicated regulation of cardiac fibrosis. It also underscores the need for more investigation into the mechanisms of cardiac fibrosis to develop better diagnostic modalities and therapeutic options in heart failure.

Abstract 10: Antifibrotic Effect of CCN5 in a Murine Model of Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dongtak Jeong ◽  
Changwon Kho ◽  
Ahyoung Lee ◽  
Woo Jin Park ◽  
Roger Hajjar
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Heart Function ◽  
Pcr Analysis ◽  
Tgf Beta ◽  
Human Heart Failure ◽  
Ccn Family

CCN family members are matricellular proteins with diverse roles in cell function. Recently, we showed that the differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. Since it is reported that an underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart, we aimed to evaluate the role of CCN5 on cardiac fibrosis and function by the gene delivery using the cardiotropic AAV9 vector. We generated pressure-overload heart failure models in mouse by TAC operation. After 8-10 weeks of TAC on mice, HF was confirmed by Echocardiography. In those HF mice, AAV9-GFP (control) and AAV9-CCN5 were addressed by IV. Two more months later, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of CCN5, several types of collagen and conventional TGF-beta signaling related genes were evaluated by western blot and quantitative real time PCR analysis. First, we were able to achieve about 4-5 fold increase of CCN5 expression by AAV9-CCN5 injection without any change in heart function. Second, CCN5 expression level in blood was not significantly altered after AAV9-CCN5 gene transfer because it may be the result of the cardiac tropism of the vector used. The HF model by TAC surgery was confirmed with echocardiography (FS (%)). Overall average FS (%) in HF was 41.87+/− 5.27 (n=16) and in non-surgery control mice was 58.39 +/− 2.06(n=4). After AAV9 injection, cardiac function of CCN5 injected mice was sustained but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (24.29+/− 9.11) vs AAV-CCN5 (42.66 +/− 4.73)). Third, western blot analysis showed that the downstream effectors, namely TGF-beta signaling pathways were significantly down-regulated in CCN5 injected mice. In addition, fibrotic area of the heart was tremendously reduced. Finally, CCN5 expression is significantly decreased in human heart failure patients compared to those in nonfailing donors. Taken together our data would indicate that CCN5 may be a promising therapeutic target to reduce cardiac fibrosis.

scholarly journals Targeting CCN Proteins in Rheumatoid Arthritis and Osteoarthritis

2021 ◽  
Vol 22 (9) ◽  
pp. 4340
Author(s):  
Iona J. MacDonald ◽  
Chien-Chung Huang ◽  
Shan-Chi Liu ◽  
Yen-You Lin ◽  
Chih-Hsin Tang
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Wound Healing ◽  
Evidence Base ◽  
Ccn Proteins ◽  
Matricellular Proteins ◽  
Substantial Evidence ◽  
Ccn Family ◽  
Cellular Processes

The CCN family of matricellular proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1-2-3/CCN4-5-6) are essential players in the key pathophysiological processes of angiogenesis, wound healing and inflammation. These proteins are well recognized for their important roles in many cellular processes, including cell proliferation, adhesion, migration and differentiation, as well as the regulation of extracellular matrix differentiation. Substantial evidence implicates four of the proteins (CCN1, CCN2, CCN3 and CCN4) in the inflammatory pathologies of rheumatoid arthritis (RA) and osteoarthritis (OA). A smaller evidence base supports the involvement of CCN5 and CCN6 in the development of these diseases. This review focuses on evidence providing insights into the involvement of the CCN family in RA and OA, as well as the potential of the CCN proteins as therapeutic targets in these diseases.

Mineralocorticoid receptor activation and cardiac fibrosis

2007 ◽  
Vol 112 (9) ◽  
pp. 467-475 ◽  
Author(s):  
Morag J. Young ◽  
Emily Y. M. Lam ◽  
Amanda J. Rickard
Keyword(s):  
Heart Failure ◽  
Mineralocorticoid Receptor ◽  
Large Scale ◽  
Best Practice ◽  
Cardiac Fibrosis ◽  
Vascular Inflammation ◽  
Severe Heart Failure ◽  
Receptor Activation ◽  
Elevated Plasma ◽  
Cardioprotective Effects

MR (mineralocorticoid receptor) activation by either administration of exogenous mineralocorticoids or by allowing endogenous glucocorticoids to activate the MR has been shown to produce oxidative stress and vascular inflammation at the earliest stages of the development of cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice therapy for moderate-to-severe heart failure and heart failure post-myocardial infarction. Given that few patients had elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated.

scholarly journals Thrombospondin module 1 domain (TSP1) of the matricellular protein CCN3 shows an atypical disulfide pattern and incomplete CWR layers

2019 ◽  
Author(s):  
Emma-Ruoqi Xu ◽  
Aleix Lafita ◽  
Alex Bateman ◽  
Marko Hyvönen
Keyword(s):  
Bone Development ◽  
Heparan Sulphate ◽  
Cell Signalling ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Ccn Family ◽  
X Ray Crystallography ◽  
Extracellular Matrix Components ◽  
Wide Range ◽  
Definition Of

AbstractMembers of the CCN (Cyr61/CTGF/Nov) family are a group of matricellular regulatory proteins, essential to a wide range of functional pathways in cell signalling. Through interacting with extracellular matrix components and growth factors via one of its four domains, the CCN proteins are involved in critical biological processes such as angiogenesis, cell proliferation, bone development, fibrogenesis, and tumorigenesis. We present here the crystal structure of the thrombospondin module 1 (TSP1) domain of CCN3 (previously known as Nov), which shares a similar three-stranded fold with the thrombospondin type 1 repeats of thrombospondin-1 and Spondin-1, but with variations in the disulfide connectivity. Moreover, the CCN3 TSP1 lacks the typical pi-stacked ladder of charged and aromatic residues on one side of the domain, as seen in other TSP1 domains. Using conservation analysis among orthologous domains, we show that a charged cluster in the centre of the domain is the most conserved site and predict it to be a potential functional epitope for heparan sulphate binding. This variant TSP1 domain has also been used to revise the sequence determinants of TSP1 domains and derive improved Pfam sequence profiles for identification of novel TSP1 domains in more than 10,000 proteins across diverse phyla.SynopsisThe first structure of a thrombospondin module 1 domain (TSP1) from a CCN family matricellular protein has been determined by X-ray crystallography. The structure shows a typical three-stranded fold, but with an incomplete pi-stacked structure that is usually found in these domains. The structure reveals highest conservation in the positively charged central segment, which we predict to be a binding site for heparan sulphates. The atypical features of this domain have been used to revise the definition of the TSP1 domains and identify a number of new domains in sequence databases.

scholarly journals Potential Role of CCN Proteins in Breast Cancer: Therapeutic Advances and Perspectives

2021 ◽  
Vol 28 (6) ◽  
pp. 4972-4985
Author(s):  
Kazi Ahsan Ahmed ◽  
Tasnin Al Hasib ◽  
Shamrat Kumar Paul ◽  
Md. Saddam ◽  
Afsana Mimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multiple Roles ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Biological Interactions ◽  
Ccn Family ◽  
Dual Nature ◽  
Functional Activities ◽  
And Migration

CCNs are a specific type of matricellular protein, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members, which exist only in vertebrates. The architecture of CCN proteins is multi-modular comprising four distinct modules. CCN Proteins achieve their primary functional activities by binding with several integrin7 receptors. The CCN family has been linked to cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, chondrogenesis, and wound healing, among other biological interactions. Breast cancer is the most commonly diagnosed cancer worldwide and CCN regulated breast cancer stands at the top. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. The pro-tumorigenic CCN1, CCN2, CCN3, and CCN4 may lead to human breast cancer, although the anti-tumorigenic actions of CCN5 and CCN6 are also present. Several studies have been conducted on CCN proteins and cancer in recent years. CCN1 and CCN3 have been shown to exhibit a dual nature of tumor inhibition and tumor suppression to some extent in quiet recent time. Pharmacological advances in treating breast cancer by targeting CCN proteins are also reported. In our study, we intend to provide an overview of these research works while keeping breast cancer in focus. This information may facilitate early diagnosis, early prognosis and the development of new therapeutic strategies.

scholarly journals Osteopontin: A Promising Therapeutic Target in Cardiac Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1558 ◽  
Author(s):  
Iman Abdelaziz Mohamed ◽  
Alain-Pierre Gadeau ◽  
Anwarul Hasan ◽  
Nabeel Abdulrahman ◽  
Fatima Mraiche
Keyword(s):  
Heart Failure ◽  
Tissue Regeneration ◽  
Cardiac Remodeling ◽  
Therapeutic Target ◽  
Cardiac Fibrosis ◽  
Matricellular Protein ◽  
Physiological Conditions ◽  
Intracellular Signals ◽  
Promising Therapeutic Target

Osteopontin (OPN) is recognized for its significant roles in both physiological and pathological processes. Initially, OPN was recognized as a cytokine with pro-inflammatory actions. More recently, OPN has emerged as a matricellular protein of the extracellular matrix (ECM). OPN is also known to be a substrate for proteolytic cleavage by several proteases that form an integral part of the ECM. In the adult heart under physiological conditions, basal levels of OPN are expressed. Increased expression of OPN has been correlated with the progression of cardiac remodeling and fibrosis to heart failure and the severity of the condition. The intricate process by which OPN mediates its effects include the coordination of intracellular signals necessary for the differentiation of fibroblasts into myofibroblasts, promoting angiogenesis, wound healing, and tissue regeneration. In this review, we discuss the role of OPN in contributing to the development of cardiac fibrosis and its suitability as a therapeutic target.

scholarly journals Dynamic molecular and histopathological changes in the extracellular matrix and inflammation in the transition to heart failure in isolated volume overload

2011 ◽  
Vol 300 (6) ◽  
pp. H2251-H2260 ◽  
Author(s):  
Yuan-wen Chen ◽  
Betty Pat ◽  
James D. Gladden ◽  
Junying Zheng ◽  
Pamela Powell ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Systolic Heart Failure ◽  
Volume Overload ◽  
Fold Increase ◽  
Left Ventricular ◽  
Matricellular Protein ◽  
Peroxisome Proliferator ◽  
Mitochondrial Enzymes

Left ventricular (LV) volume overload (VO) causes eccentric remodeling with inflammatory cell infiltration and extracellular matrix (ECM) degradation, for which there is currently no proven therapy. To uncover new pathways that connect inflammation and ECM homeostasis with cellular dysfunction, we determined the cardiac transciptome in subacute, compensated, and decompensated stages based on in vivo hemodynamics and echocardiography in the rat with aortocaval fistula (ACF). LV dilatation at 5 wk was associated with a normal LV end-diastolic dimension-to-posterior wall thickness ratio (LVEDD/PWT; compensated), whereas the early 2-wk (subacute) and late 15-wk (decompensated) ACF groups had significant increases in LVEDD/PWT. Subacute and decompensated stages had a significant upregulation of genes related to inflammation, the ECM, the cell cycle, and apoptosis. These changes were accompanied by neutrophil and macrophage infiltration, nonmyocyte apoptosis, and interstitial collagen loss. At 15 wk, there was a 40-fold increase in the matricellular protein periostin, which inhibits connections between collagen and cells, thereby potentially mediating a side-to-side slippage of cardiomyocytes and LV dilatation. The majority of downregulated genes was composed of mitochondrial enzymes whose suppression progressed from 5 to 15 wk concomitant with LV dilatation and systolic heart failure. The profound decrease in gene expression related to fatty acid, amino acid, and glucose metabolism was associated with the downregulation of peroxisome proliferator associated receptor (PPAR)-α-related and bioenergetic-related genes at 15 wk. In VO, an early phase of inflammation subsides at 5 wk but reappears at 15 wk with marked periostin production along with the suppression of genes related to PPAR-α and energy metabolism.

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