Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts

Tank, Juliane; Lindner, Diana; Wang, Xiaomin; Stroux, Andrea; Gilke, Leona; Gast, Martina; Zietsch, Christin; Skurk, Carsten; Scheibenbogen, Carmen; Klingel, Karin; Laßner, Dirk; Kühl, Uwe; Schultheiss, Heinz‐Peter; Westermann, Dirk; Poller, Wolfgang

doi:10.1016/j.yjmcc.2013.11.004

Cited by 37 publications

(32 citation statements)

References 65 publications

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“…Overall, the dysregulation of myomiR expression in muscle degenerative diseases was demonstrated to be intrinsic to the disease progression. In diseased cardiac tissues, preinflammatory reactions involve upregulation of CNN genes, and in vitro the downregulation of CNN2 blocks multiple proinflammatory and profibrotic pathways in mouse activated primary cardiac fibroblasts (PCFBs) [65] .…”

Section: Inflammationmentioning

confidence: 99%

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

136

132

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MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/ tissue regeneration/tissue inflammation responses, and cancer development. Core tip: The roles of the canonical muscle-associated microRNAs are reviewed, including microRNA families miR-1 and miR-133, and single miR-206, which are collectively known as the "myomiRs". The myomiRs act at the crossroads of the molecular regulation of muscle cells, linking between pathways for cell differentiation, development and maintenance, but also potentiate aberrant cell growth in numerous non-muscle cancers. Typically myomiRs are downregulated in cancers, but some myomiRs are upregulated in a few cancers, yet each dysregulation event advances tumor progression. The review examines normal and disease-linked molecular changes associated with the myomiRs, and collates the extensive literature into accessible tables. REVIEW

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Section: Inflammationmentioning

confidence: 99%

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

136

132

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“…81 CCN2 silencing using small interfering RNA of activated primary cardiac fibroblasts resulted in strongly reduced expression of stretch-induced chemokines (Ccl2, Ccl7, and Ccl8), matrix metalloproteinases (MMP2 and MMP9), ECM (Col3a1), and a cell-to-cell contact protein (Cx43). 82 Ang-II-induced expression of hypertrophic marker genes or collagens was not affected by treatment with anti-CCN2 monoclonal antibodies, whereas anti-CCN2 monoclonal antibodies caused resistance to adverse LV remodeling and LV dysfunction in hearts resulting from pressure overload caused by thoracic aortic constriction. 83 Conversely, when a thoracic aortic constriction model was used, anti-CCN2 antibodies reduced both collagen levels and hypertrophic marker gene expression, reduced cardiomyocyte crosssectional area and LV dilatation, and preserved LV systolic function.…”

Section: Ccn2mentioning

confidence: 88%

Getting to the Heart of the Matter

Leask

2015

Circulation Research

292

147

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Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.

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“…Another study on the same model found that ACE inhibition reduced muscle damage and ECM accumulation by inhibiting the expression of CCN2 (9). Interestingly, RNA interference silencing CCN2 in activated primary cardiac fibroblasts was found to block multiple pro-inflammatory and pro-fibrotic pathways, demonstrating that CCN2 is a central regulator in these processes (10).…”

Section: Matricellular Proteins In Fibrotic Diseasesmentioning

confidence: 96%