The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling

Lee, Min-Ah; Raad, Nour; Song, Min Ho; Yoo, Jimeen; Lee, Mi-Young; Jang, Seung Pil; Kwak, Tae Hwan; Kook, Hyun; Choi, Eun Seo; Cha, Tae-Joon; Hajjar, Roger J.; Jeong, Dongtak; Park, Woo Jin

doi:10.1111/jcmm.15789

Cited by 6 publications

(9 citation statements)

References 34 publications

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“…Thus, neutrophils are recruited to the ischemic area and exert potent cytotoxic effects by releasing proteolytic enzymes that affect cardiomyocytes [38]. In this regard, our group has shown in a previous study that CCN5 exhibits anti-inflammatory activity [41,42]. For example, CCN5 knockout mice highly expressed proinflammatory genes in mice with lipotoxic cardiomyopathy [41].…”

Section: Discussionmentioning

confidence: 99%

Modified mRNA Mediated CCN5 Gene Transfer Ameliorates Cardiac Dysfunction and Fibrosis without Adverse Structural Remodeling

Song,

Yoo,

Kwon

et al. 2024

Preprint

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Modified mRNAs (modRNAs) are an emerging delivery method for gene therapy. In particular, the modRNA-based COVID-19 vaccines have proven that modRNA is a safe and effective therapeutic tool. Moreover, modRNA has the potential to treat various human diseases including cardiac dysfunction. Acute myocardial infarction (MI) is a major cardiac disorder that currently lacks curative treatment options. MI is commonly accompanied by fibrosis and impaired cardiac function. Our group previously demonstrated that the matricellular protein CCN5 inhibits cardiac fibrosis (CF) and improves cardiac dysfunction. However, it remains elusive whether the early intervention of CF under stress conditions is beneficial or more detrimental due to potential adverse effects such as left ventricular (LV) rupture. To obtain acute CCN5 expression, we used modRNA-mediated gene transfer in a mouse MI model. To evaluate CCN5 activity, we established two independent experimental schemes: 1) preventive intervention and 2) therapeutic intervention. Cardiac function and structural changes were measured by echocardiography and magnetic resonance imaging. Finally, fibrosis and the underlying molecular pathway were analyzed by western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The modRNA-CCN5 gene transfer successfully ameliorated CF and enhanced cardiac function in both preventive and therapeutic interventions without LV rupture or any adverse cardiac remodeling. Conclusively, early intervention in CF by modRNA-CCN5 gene transfer is an efficient and safe therapeutic modality for treating MI-induced heart failure without adverse structural remodeling.

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Section: Discussionmentioning

confidence: 99%

Modified mRNA Mediated CCN5 Gene Transfer Ameliorates Cardiac Dysfunction and Fibrosis without Adverse Structural Remodeling

Song,

Yoo,

Kwon

et al. 2024

Preprint

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“…This involves both enlargement of the atria and fibrosis, adversely affecting atrial conduction and resulting in AF. 7,33 The left atrium is critically involved in both the recurrence and continuation of AF. 34 AF can result in left atrial dilation, which is thought to play a part in structural remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…34 Structural remodeling is also closely linked with fibrosis of the atrium, interfering with normal electrophysiological activity of the myocardium, preventing normal atrial activation, slowing atrial conduction, and leading to disorganized or asynchronous conduction. 7 Fibrosis is associated with increased collagen accumulation, 36 and it has been reported in both animals and humans that such accumulation is caused by AF. 33 A study comparing structural remodeling between AF-affected and healthy horses found elevated collagen deposition in horses with AF, with more marked differences in the left, rather than the right atrium.…”

Section: Discussionmentioning

confidence: 99%

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Vericiguat reduces electrical and structural remodeling in a rabbit model of atrial fibrillation

Lou

Liu

et al. 2023

J Cardiovasc Pharmacol Ther

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Purpose: The molecular etiology of atrial fibrillation (AF) and its treatment are poorly understood. AF involves both electrical and structural features. Vericiguat can ameliorate cardiac remodeling in heart failure. The effects of vericiguat on AF, however, are unclear. Here, the actions of vericiguat on atrial structural and electrical remodeling in AF and its possible mechanisms were investigated. Methods and Results: Thirty-six rabbits were randomly allocated to four groups, namely, sham, RAP (pacing with 600 beats/min over three weeks), vericiguat-treated (three weeks’ pacing plus daily oral dose of 1.5 mg/kg of vericiguat), and vericiguat-treated only. HL-1 cells received rapid pacing with or without vericiguat. Parameters including electrophysiology, echocardiography, histology, Ca2+ levels, and ICaL density, as well as levels of TRPC6, CaN, NFAT4, p-NFAT4, Cav1.2, collagen I, collagen III, and ST2 were measured. Significant changes of above proteins expression level, circulating biochemical indices, Ca2+ concentrations, and ICaL density in both animals and cell models, these effects were significantly restored by vericiguat. Vericiguat also reversed the enlarged atrium and significantly reduced myocardial fibrosis, together with preventing reduced atrial effective refractory periods (AERPs) and AF induction rate. Conclusion: Vericiguat thus ameliorated AF-associated structural and electrical remodeling. These findings suggest the potential of vericiguat for treating AF.

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“…Thus, CCN5 may be a potential biomarker for estimating cardiac fibrosis in hypertensive patients. Based on these findings, CCN5 could be a novel therapeutic target that should be developed for stimulating endogenous CCN5 production (Huang et al 2020; Lee et al 2020; Song et al 2022).…”

Section: The Physiological Roles Of Ccn‐family Proteins In Healthy Ti...mentioning

confidence: 99%

The role of CCNs in controlling cellular communication in the tumor microenvironment

Birkeness

Banerjee

Quadir

2022

J. Cell Commun. Signal.

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The Cellular communication network (CCN) family of growth regulatory factors comprises six secreted matricellular proteins that promote signal transduction through cell-cell or cell-matrix interaction. The diversity of functionality between each protein is specific to the many aspects of healthy and cancer biology. For example, CCN family proteins modulate cell adhesion, proliferation, migration, invasiveness, apoptosis, and survival. In addition, the expression of each protein regulates many biological and pathobiological processes within its microenvironment to regulate angiogenesis, inflammatory response, chondrogenesis, fibrosis, and mitochondrial integrity. The collective range of CCN operation remains fully comprehended; however, understanding each protein's microenvironment may draw more conclusions about the abundance of interactions and signaling cascades occurring within such issues. This review observes and distinguishes the various roles a CCN protein may execute within distinct tumor microenvironments and the biological associations among them. Finally. We also review how CCN-family proteins can be used in nano-based therapeutic implications.

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The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 34 publications

Modified mRNA Mediated CCN5 Gene Transfer Ameliorates Cardiac Dysfunction and Fibrosis without Adverse Structural Remodeling

Modified mRNA Mediated CCN5 Gene Transfer Ameliorates Cardiac Dysfunction and Fibrosis without Adverse Structural Remodeling

Vericiguat reduces electrical and structural remodeling in a rabbit model of atrial fibrillation

The role of CCNs in controlling cellular communication in the tumor microenvironment

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