Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

Liu, Liang; Tu, Yalin; Lu, Jing; Wang, Panxia; Guo, Zhen; Wang, Qianqian; Guo, Kaiteng; Lan, Rui; Li, Hong

doi:10.1242/jcs.228478

Cited by 31 publications

(22 citation statements)

References 32 publications

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“…Wnt/β‐catenin signalling has been reported to be an inducer for cardiac hypertrophy, and inactivation of this signalling ameliorated hypertensive heart disease . It is reported Dkk1 inhibits Wnt signalling to regulate early myocardial proliferation Dkk1 exacerbates doxorubicin‐induced cardiotoxicity by inhibiting the Wnt/β‐catenin signalling pathway . It is indicating a significant role of DKK1 in the heart diseases.…”

Section: Resultsmentioning

confidence: 99%

LncRNA TUG1 alleviates cardiac hypertrophy by targeting miR‐34a/DKK1/Wnt‐β‐catenin signalling

Fang

Liu

et al. 2020

J Cellular Molecular Medi

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Cardiac hypertrophy, classified as physiological and pathological hypertrophy, is an adaptive response of the heart to keep normal cardiac function in the condition of pathological injury or abnormal stress. 1 Physiological cardiac hypertrophy, caused by pregnancy or sports training, has normal morphological characteristics and helpful influences on the heart. 2 Pathological cardiac hypertrophy, accompanied by maladaptive cardiac remodelling, altered cardiac morphology as well as abnormal cardiac gene expressions, is the key induction factor for heart failure progression. 3 Although many factors have been confirmed to induce cardiac hypertrophy, 4 the underlying molecular mechanisms have not been stated clearly. LncRNAs, a series of highly conserved non-coding RNAs, are composed of more than 200 nucleotides. 5,6 With continuous advances in sequencing technology and large-scale genome sequencing projects, Abstract The current study was designed to explore the role and underlying mechanism of lncRNA taurine up-regulated gene 1 (TUG1) in cardiac hypertrophy. Mice were treated by transverse aortic constriction (TAC) surgery to induce cardiac hypertrophy, and cardiomyocytes were treated by phenylephrine (PE) to induce hypertrophic phenotype. Haematoxylin-eosin (HE), wheat germ agglutinin (WGA) and immunofluorescence (IF) were used to examine morphological alterations. Real-time PCR, Western blots and IF staining were used to detect the expression of RNAs and proteins. Luciferase assay and RNA pull-down assay were used to verify the interaction. It is revealed that TUG1 was up-regulated in the hearts of mice treated by TAC surgery and in PE-induced cardiomyocytes. Functionally, overexpression of TUG1 alleviated cardiac hypertrophy both in vivo and in vitro. Mechanically, TUG1 sponged and sequestered miR-34a to increase the Dickkopf 1 (DKK1) level, which eventually inhibited the activation of Wnt/β-catenin signalling.In conclusion, the current study reported the protective role and regulatory mechanism of TUG1 in cardiac hypertrophy and suggested that TUG1 may serve as a novel molecular target for treating cardiac hypertrophy. K E Y W O R D Scardiac hypertrophy, DKK 1, lncRNA TUG1, miR-34a, Wnt/β-catenin signalling

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Section: Resultsmentioning

confidence: 99%

LncRNA TUG1 alleviates cardiac hypertrophy by targeting miR‐34a/DKK1/Wnt‐β‐catenin signalling

Fang

Liu

et al. 2020

J Cellular Molecular Medi

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“…With regard to molecular mechanisms, our results indicate that the effects of TGFβ1 on bone mineralization may involve DKK1, which is a secreted protein originally located within the endoplasmic reticulum (ER) in the cytoplasm. Several studies have found that ER stress induces DKK1 secretion, eventually leading to cell apoptosis [ 35 , 36 , 37 ]. Osteoblasts can either transform when they are embedded in bone as osteocytes or undergo apoptosis for bone mineralization at the end phase of bone formation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis

Nam

Park

Lee

et al. 2020

IJMS

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Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFβ1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPβ) were dramatically suppressed by TGFβ1 treatment. The suppressive effects of TGFβ1 were reversed with anti-TGFβ1 treatment. Mechanically, TGFβ1 decreased protein levels of C/EBPβ without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPβ protein by TGFβ1 was dependent on the ubiquitin–proteasome pathway. TGFβ1 degraded the C/EBPβ protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPβ-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFβ1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPβ-DKK1 axis.

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“…Lin28a overexpression significantly decreased RhoA/ROCK signaling to alleviate mitochondria cristae destruction and promote heart function in diabetic mice (Sun et al, 2016). Additionally, Dkk1 adenovirus is transduced by intramyocardial injection, and Dkk1 overexpression aggravates Dox-induced CM apoptosis via the mitochondrial damage pathway (Liang et al, 2019). AAV serotype 9 (AAV-9) Plscr4, lncRNA-Plscr4 overexpression attenuates the hypertrophic response in hyperpressure-loaded CMs (Liu et al, 2020).…”

Section: Gene Editing For Genetic Disordermentioning

confidence: 99%

Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes

Liao

Yan

et al. 2021

Front. Cell Dev. Biol.

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Mitochondria are one of the most important organelles in cardiomyocytes. Mitochondrial homeostasis is necessary for the maintenance of normal heart function. Mitochondria perform four major biological processes in cardiomyocytes: mitochondrial dynamics, metabolic regulation, Ca2+ handling, and redox generation. Additionally, the cardiovascular system is quite sensitive in responding to changes in mechanical stress from internal and external environments. Several mechanotransduction pathways are involved in regulating the physiological and pathophysiological status of cardiomyocytes. Typically, the extracellular matrix generates a stress-loading gradient, which can be sensed by sensors located in cellular membranes, including biophysical and biochemical sensors. In subsequent stages, stress stimulation would regulate the transcription of mitochondrial related genes through intracellular transduction pathways. Emerging evidence reveals that mechanotransduction pathways have greatly impacted the regulation of mitochondrial homeostasis. Excessive mechanical stress loading contributes to impairing mitochondrial function, leading to cardiac disorder. Therefore, the concept of restoring mitochondrial function by shutting down the excessive mechanotransduction pathways is a promising therapeutic strategy for cardiovascular diseases. Recently, viral and non-viral protocols have shown potentials in application of gene therapy. This review examines the biological process of mechanotransduction pathways in regulating mitochondrial function in response to mechanical stress during the development of cardiomyopathy and heart failure. We also summarize gene therapy delivery protocols to explore treatments based on mechanical stress–induced mitochondrial dysfunction, to provide new integrative insights into cardiovascular diseases.

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Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

Cited by 31 publications

References 32 publications

LncRNA TUG1 alleviates cardiac hypertrophy by targeting miR‐34a/DKK1/Wnt‐β‐catenin signalling

LncRNA TUG1 alleviates cardiac hypertrophy by targeting miR‐34a/DKK1/Wnt‐β‐catenin signalling

TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis

Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes

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