Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy

Zhong, Lin; Chiusa, Manuel; Cadar, Adrian G; Lin, Alex T.L.; Samaras, Susan; Davidson, Jeffrey M.; Lim, Chee Chew

doi:10.1093/cvr/cvv108

Cited by 58 publications

(71 citation statements)

References 40 publications

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“…MARP1 binds to titin's elastic N2A region (Figure 6). MARP proteins have been proposed to be stretch responsive9 and have been implicated in hypertrophy signalling, through interaction with the Erk‐GATA4 complex 48. As following UDD MARP1 shows no evidence of nuclear localization (Figure 6A–F), therefore interaction with GATA4 is unlikely.…”

Section: Discussionmentioning

confidence: 97%

Titin‐based mechanosensing modulates muscle hypertrophy

Pijl

Strom

Conijn

et al. 2018

J cachexia sarcopenia muscle

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BackgroundTitin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing.MethodsWe used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs.ResultsIn wildtype mice, the denervated hemidiaphragm mass increased 48 ± 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20ΔRRM and TtnΔIAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20ΔRRM mice (reduced stiffness) showed a 20 ± 6% attenuated hypertrophy response, whereas the TtnΔIAjxn mice (increased stiffness) showed an 18 ± 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin‐binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1.ConclusionsTitin functions as a mechanosensor that regulates muscle trophicity.

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Section: Discussionmentioning

confidence: 97%

Titin‐based mechanosensing modulates muscle hypertrophy

Pijl

Strom

Conijn

et al. 2018

J cachexia sarcopenia muscle

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“…Multiple studies demonstrated that the activity of C/EBP β, c-Fos and HIF-1αis also regulated by posttranslational modification caused by phosphorylation by different kinases, such as MAPK, cdc2, PKA and PKC1617484950. Previous studies targeted the effects of ERK1/2 pathways on GPR91-dependent VEGF expression in the retinas of streptozotocin-induced diabetic rats7.…”

Section: Discussionmentioning

confidence: 99%

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Gao

et al. 2017

Sci Rep

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Hypoxia is the most important factor in the pathogenesis of diabetic retinopathy (DR). Our previous studies demonstrated that G protein-coupled receptor 91(GPR91) participated in the regulation of vascular endothelial growth factor (VEGF) secretion in DR. The present study induced OIR model in newborn rats using exposure to alternating 24-hour episodes of 50% and 12% oxygen for 14 days. Treatment with GPR91 shRNA attenuated the retinal avascular area, abnormal neovascularization and pericyte loss. Western blot and qRT-PCR demonstrated that CoCl2 exposure promoted VEGF expression and secretion, activated the ERK1/2 signaling pathways and upregulated C/EBP and AP-1. Knockdown of GPR91 inhibited ERK1/2 activity. GPR91 siRNA transduction and the ERK1/2 inhibitor U0126 inhibited the increases in C/EBP β, C/EBP δ, c-Fos and HIF-1α. Luciferase reporter assays and a chromatin immunoprecipitation (ChIP) assay demonstrated that C/EBP β and c-Fos bound the functional transcriptional factor binding site in the region of the VEGF promoter, but not C/EBP δ. Knockdown of C/EBP β and c-Fos using RNAi reduced VEGF expression. Our data suggest that activation of the GPR91-ERK1/2-C/EBP β (c-Fos, HIF-1α) signaling pathway plays a tonic role in regulating VEGF transcription in rat retinal ganglion cells.

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“…Since we have validated the protective roles of ACE3 in response to Ang II‐ and pressure overload‐induced cardiac hypertrophy, it has significance to test whether ACE3 can also affect other types of cardiac hypertrophy, such as the adrenergic receptor‐induced cardiac hypertrophy. Among the multiple signaling pathways that activated by the adrenergic receptors, a large body of evidence has showed the essential roles of the ERK1/2 signaling during different adrenergic receptor‐induced hypertrophic response 25, 26. As we have demonstrated the anti‐hypertrophic effects of ACE3 are mainly depend on inhibition of the MEK‐ERK1/2 signaling, it is likely that ACE3 can also function as a negative regulator in adrenergic receptor‐induced hypertrophy.…”

Section: Discussionmentioning

confidence: 69%

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

Tang

Chen

et al. 2016

JAHA

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BackgroundAngiotensin‐converting enzyme 3 (ACE3) is a recently defined homolog of ACE. However, the pathophysiological function of ACE3 is largely unknown. Here, we aim to explore the role of ACE3 in pathological cardiac hypertrophy.Methods and ResultsNeonatal rat cardiomyocytes (NRCMs) with gain and loss of function of ACE3 and mice with global knockout or cardiac‐specific overexpression of ACE3 were used in this study. In cultured cardiomyocytes, ACE3 conferred protection against angiotensin II (Ang II)‐induced hypertrophic growth. Cardiac hypertrophy in mice was induced by aortic banding (AB) and the extent of hypertrophy was analyzed through echocardiographic, pathological, and molecular analyses. Our data demonstrated that ACE3‐deficient mice exhibited more pronounced cardiac hypertrophy and fibrosis and a strong decrease in cardiac contractile function, conversely, cardiac‐specific ACE3‐overexpressing mice displayed an attenuated hypertrophic phenotype, compared with control mice, respectively. Analyses of the underlying molecular mechanism revealed that ACE3‐mediated protection against cardiac hypertrophy by suppressing the activation of mitogen‐activated protein kinase kinase (MEK)‐regulated extracellular signal‐regulated protein kinase (ERK1/2) signaling, which was further evidenced by the observation that inhibition of the MEK‐ERK1/2 signaling by U0126 rescued the exacerbated hypertrophic phenotype in ACE3‐deficient mice.ConclusionsOur comprehensive analyses suggest that ACE3 inhibits pressure overload‐induced cardiac hypertrophy by blocking the MEK‐ERK1/2 signaling pathway.

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Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy

Cited by 58 publications

References 40 publications

Titin‐based mechanosensing modulates muscle hypertrophy

Titin‐based mechanosensing modulates muscle hypertrophy

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

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