Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts

George, Mereena; Vijayakumar, Anupama; Dhanesh, Sivadasan Bindu; James, Jackson; Shivakumar, K.

doi:10.1016/j.yjmcc.2015.12.004

Cited by 40 publications

(54 citation statements)

References 58 publications

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“…Recently, ANG II-induced expression of the collagen-specific tyrosine kinase receptor discoidin domain receptor 2 (DDR2) in cardiac fibroblasts was linked to activation of NF-B by p38MAPK, downstream of PLC and PKC activation, which in turn are linked to NADPH oxidase-dependent ROS generation. Intriguingly, DDR2 is critical for ANG II-induced ERK1/2 activation and subsequent collagen expression (314).…”

Section: Src Transcriptional Factors and Mapk Familymentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

816

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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Section: Src Transcriptional Factors and Mapk Familymentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

816

780

View full text Add to dashboard Cite

show abstract

“…Discoidin domain receptor 2 (Ddr2) is a tyrosine kinase receptor that is expressed on the surface of cells of mesenchymal origin (33,34). It plays a marked regulatory role in EMT and is associated with fibrotic diseases because it is a collagen-specific receptor (34). Ddr2 was long believed to be a specific marker of cardiac fibroblasts.…”

Section: Discoidin Domain Receptormentioning

confidence: 99%

Cardiac fibroblasts: more than mechanical support

et al. 2017

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Fibroblasts are cells with a structural function, synthesizing components of the extracellular matrix. They are accordingly associated with various forms of connective tissue. During cardiac development fibroblasts originate from different sources. Most derive from the epicardium, some derive from the endocardium, and a small population derives from the neural crest. Cardiac fibroblasts have important functions during development, homeostasis, and disease. However, since fibroblasts are a very heterogeneous cell population no truly specific markers exist. Therefore, studying them in detail is difficult. Nevertheless, several lineage tracing models have been widely used. In this review, we describe the developmental origins of cardiac fibroblasts, comment on fibroblast markers and related lineage tracing approaches, and discuss the cardiac cell composition, which has recently been revised, especially in terms of non-myocyte cells.

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“…The receptor gains its unique place by functioning as a sensor for collagen and by participating in migration, proliferation, and extracellular matrix remodeling. The expression of DDR2 had been previously observed in the development of tissue, homeostasis, response to injury, and tumorigenesis [7, 8]. …”

Section: Introductionmentioning

confidence: 99%

DDR2 overexpression in urothelial carcinoma indicates an unfavorable prognosis: a large cohort study

Tsai

Huang

et al. 2016

Oncotarget

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The migration ability of urothelial carcinoma corresponding to dismal prognosis had not been fully investigated. The interaction of extracellular collagen with a unique transmembrane receptor tyrosine kinase, Discoidin domain receptor 2 (DDR2), was selected by data mining. We arranged real-time reverse transcription polymerase chain reaction assays to evaluate the transcript levels in 26 urinary tract urothelial carcinoma and 26 urinary bladder urothelial carcinoma specimens, showing significantly increase corresponding to advanced primary stage (p = 0.003 and p < 0.001, respectively). An immunohistochemistry analysis and H-score calculation were performed to determine DDR2 expression in 340 urinary tract urothelial carcinoma and 295 urinary bladder urothelial carcinoma. Assessments of the correlation to clinicopathologic features, disease-specific survival, and metastasis-free survival were conducted. The transcript levels in advanced stage were higher than those in early stage and were correlated with poor prognosis. The higher expression was positively correlated to higher pT status (p < 0.001), higher histological grade (urinary tract, p = 0.041; urinary bladder, p < 0.001), greater vascular invasion (p < 0.001), and higher mitotic rate (urinary tract, p = 0.039; urinary bladder, p < 0.001). Higher expression also indicates significantly worse disease-specific survival and metastasis-free survival. In vitro study revealed knockdown of DDR2 resulted in a depletion of cellular viability, migratory, and invasive ability, supporting the oncogenic function of DDR2.

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Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts

Cited by 40 publications

References 58 publications

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Cardiac fibroblasts: more than mechanical support

DDR2 overexpression in urothelial carcinoma indicates an unfavorable prognosis: a large cohort study

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