Expression and distribution of Src in the nucleus of myocytes in cardiac hypertrophy

Chen, Ping; Li, Faqian; Xu, Zhiyong; Li, Zhanyu; Yi, Xian Ping

doi:10.3892/ijmm.2013.1382

Cited by 6 publications

(4 citation statements)

References 29 publications

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“…MS-mediated autophosphorylation of Src is highly associated with ERK1/2 activation [14]. Recent study revealed the expression and distribution of Src in the nucleus of cardiomyocytes with hypertrophy [15], and β-arrestin2 enhanced nuclear localization of ERK1/2 via GPCRs activation [16]. Mutant AT1 receptor lacking the docking site impaired Src-dependent nuclear translocation of ERK1/2 [10].…”

Section: Introductionmentioning

confidence: 99%

Src Is Required for Mechanical Stretch-Induced Cardiomyocyte Hypertrophy through Angiotensin II Type 1 Receptor-Dependent β-Arrestin2 Pathways

et al. 2014

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Angiotensin II (AngII) type 1 receptor (AT1-R) can be activated by mechanical stress (MS) without the involvement of AngII during the development of cardiomyocyte hypertrophy, in which G protein-independent pathways are critically involved. Although β-arrestin2-biased signaling has been speculated, little is known about how AT1-R/β-arrestin2 leads to ERK1/2 activation. Here, we present a novel mechanism by which Src kinase mediates AT1-R/β-arrestin2-dependent ERK1/2 phosphorylation in response to MS. Differing from stimulation by AngII, MS-triggered ERK1/2 phosphorylation is neither suppressed by overexpression of RGS4 (the negative regulator of the G-protein coupling signal) nor by inhibition of Gαq downstream protein kinase C (PKC) with GF109203X. The release of inositol 1,4,5-triphosphate (IP3) is increased by AngII but not by MS. These results collectively suggest that MS-induced ERK1/2 activation through AT1-R might be independent of G-protein coupling. Moreover, either knockdown of β-arrestin2 or overexpression of a dominant negative mutant of β-arrestin2 prevents MS-induced activation of ERK1/2. We further identifies a relationship between Src, a non-receptor tyrosine kinase and β-arrestin2 using analyses of co-immunoprecipitation and immunofluorescence after MS stimulation. Furthermore, MS-, but not AngII-induced ERK1/2 phosphorylation is attenuated by Src inhibition, which also significantly improves pressure overload-induced cardiac hypertrophy and dysfunction in mice lacking AngII. Finally, MS-induced Src activation and hypertrophic response are abolished by candesartan but not by valsartan whereas AngII-induced responses can be abrogated by both blockers. Our results suggest that Src plays a critical role in MS-induced cardiomyocyte hypertrophy through β-arrestin2-associated angiotensin II type 1 receptor signaling.

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Section: Introductionmentioning

confidence: 99%

Src Is Required for Mechanical Stretch-Induced Cardiomyocyte Hypertrophy through Angiotensin II Type 1 Receptor-Dependent β-Arrestin2 Pathways

et al. 2014

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“…In the context of sympathetic nerve activation, the intertwined processes of apoptosis, hypertrophy, proliferation, and other cellular fates need to be further elucidated. In addition to the aforementioned limitations, it is worth noting that the phosphorylation of Src and its subcellular distribution play a role in signal transduction within the myocardial nucleus, representing an important process in cellular response to external stimuli [ 52 ]. Meanwhile, ERK1/2, as a crucial intracellular mediator, exerts profound effects on cell proliferation, survival, apoptosis and transdifferentiation [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Src tyrosine kinase promotes cardiac remodeling induced by chronic sympathetic activation

Li,

Zhu,

Wang

et al. 2023

Bioscience Reports

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Cardiac remodeling serves as the underlying pathological basis for numerous cardiovascular diseases and represents a pivotal stage for intervention. The excessive activation of β-adrenergic receptors (β-ARs) assumes a crucial role in cardiac remodeling. Nonetheless, the underlying molecular mechanisms governing β-AR-induced cardiac remodeling remain largely unresolved. In this study, we identified Src tyrosine kinase as a key player in the cardiac remodeling triggered by excessive β-AR activation. Our findings demonstrated that Src mediates isoproterenol (ISO)-induced cardiac hypertrophy, fibrosis, and inflammation in vivo. Furthermore, Src facilitates β-AR-mediated proliferation and transdifferentiation of cardiac fibroblasts, and hypertrophy and cardiomyocytes in vitro. Subsequent investigations have substantiated that Src mediates β-AR induced the extracellular signal-regulated protein kinase (ERK1/2) signaling pathway activated by β-AR. Our research presents compelling evidence that Src promotes β-AR-induced cardiac remodeling in both in vivo and in vitro settings. It establishes the promoting effect of the β-AR/Src/ERK signaling pathway on overall cardiac remodeling in cardiac fibroblasts and underscores the potential of Src as a therapeutic target for cardiac remodeling.

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“…The Src kinase, a non-receptor protein tyrosine kinase, plays important roles in cell proliferation, adhesion, survival, differentiation, and cell motility [31]. It is involved in a variety of signal pathways involved in cardiac hypertrophy, such as G protein coupled receptor signal transduction and integrin mediated [32]. The activity of Src kinase can be regulated by changing the phosphorylation of specific tyrosine residues.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomics analysis of diabetic cardiomyopathy in aging‐accelerated mice and effects of D‐pinitol

et al. 2021

Proteomics Clinical Apps

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Purpose:The molecular mechanisms of diabetic cardiomyopathy (DCM) development and D-pinitol (DP) in its treatment remain unclear. The present study is to explore the underlying mechanism of DCM in an elderly diabetic mouse model and to seek the protective targets of DP by phosphoproteomics. Experimental design:We used streptozotocin to induce diabetes in SAMP8 and DP (150 mg/kg/day) intragastrically administrated to diabetic mice for 8 weeks. The heart tissues were harvested for label-free phosphoproteomic analysis from diabetic mice. Some differentially regulated phosphorylation sites were confirmed by parallel reaction monitoring.Results: Our results showed that 612 phosphorylation sites on 454 proteins had their phosphorylation levels significantly changed in the heart of untreated diabetic mice (DM). Of these phosphorylation sites, 216 phosphorylation sites on 182 proteins were normalized after DP treatment. We analyzed the functional signaling pathways in the heart of DP treated diabetic mice (DMT), including glucagon signaling pathway, insulin signaling pathway, mitophagy, apoptosis, and longevity regulating pathway. Two consensus motifs identified were targeted by Src and epidermal growth factor receptor between DMT and DM groups. Conclusions and clinical relevance:Our study might help to better understand the mechanism of DCM, provide novel targets for estimating the protective effects of DP.

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Expression and distribution of Src in the nucleus of myocytes in cardiac hypertrophy

Cited by 6 publications

References 29 publications

Src Is Required for Mechanical Stretch-Induced Cardiomyocyte Hypertrophy through Angiotensin II Type 1 Receptor-Dependent β-Arrestin2 Pathways

Src Is Required for Mechanical Stretch-Induced Cardiomyocyte Hypertrophy through Angiotensin II Type 1 Receptor-Dependent β-Arrestin2 Pathways

Src tyrosine kinase promotes cardiac remodeling induced by chronic sympathetic activation

Phosphoproteomics analysis of diabetic cardiomyopathy in aging‐accelerated mice and effects of D‐pinitol

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