Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway

Zhou, Yang; Bourcy, Katherine; Kang, Yu

doi:10.1093/cvr/cvp178

Cited by 52 publications

(92 citation statements)

References 21 publications

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“…The EGFR pathway activation has been shown to contribute to the development of cardiac hypertrophy [Zhai et al, 2006;Zhou et al, 2009]. Importantly, previous studies showed silibinin could inhibit EGFR activation in various tumor cells [Ramasamy and Agarwal, 2008].…”

Section: Discussionmentioning

confidence: 99%

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

Zhang

Tang

et al. 2010

J of Cellular Biochemistry

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Cardiac hypertrophy is a major determinant of heart failure. The epidermal growth factor receptor (EGFR) plays an important role in cardiac hypertrophy. Since silibinin suppresses EGFR in vitro and in vivo, we hypothesized that silibinin would attenuate cardiac hypertrophy through disrupting EGFR signaling. In this study, we examined this hypothesis using neonatal cardiac myocytes and fibroblasts induced by angiotensin II (Ang II) and animal model by aortic banding (AB) mice. Our data revealed that silibinin obviously blocked cardiac hypertrophic responses induced by pressure overload. Meanwhile, silibinin markedly reduced the increased generation of EGFR. Moreover, these beneficial effects were associated with attenuation of the EGFR-dependent ERK1/2, PI3K/Akt signaling cascade. We further demonstrated silibinin decreased inflammation and fibrosis by blocking the activation of NF-kappaB and TGF-beta1/Smad signaling pathways in vitro and in vivo. Our results indicate that silibinin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through blocking EGFR activity and EGFR-dependent different intracellular signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

Zhang

Tang

et al. 2010

J of Cellular Biochemistry

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“…The effects of mismatched RNA on the parameters measured earlier were as same as the blank controls, thus omitted from the figures. Previous studies have shown that Cu-induced regression of cardiomyocyte hypertrophy is VEGF dependent [1][2][3]. In this context, we examined whether or not the recovery of COX activity is required for VEGF-induced regression of cardiomyocyte hypertrophy.…”

Section: Resultsmentioning

confidence: 95%

“…Further studies demonstrated that addition of physiologically relevant levels of Cu to primary cultures of neonatal rat cardiomyocytes reversed cell hypertrophy induced by phenylephrine (PE) [2,3]. Cu-induced regression of cardiomyocyte hypertrophy was VEGF-dependent both in vivo [1] and in vitro [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…(2) To determine whether COX is essential for Cu-induced regression of cell hypertrophy. (3) To probe the relationship between COX and VEGF in the regression of cardiomyocyte hypertrophy. The results obtained demonstrated that COX is essential, and VEGF is not effective without the restoration of COX activity in mediating Cu-induced regression of cardiomyocyte hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

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Cytochrome c Oxidase is Essential for Copper-Induced Regression of Cardiomyocyte Hypertrophy

et al. 2010

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Previous studies have shown that both copper (Cu) and vascular endothelial growth factor (VEGF) reduce the size of hypertrophic cardiomyocytes, but the Cu-induced regression is VEGF dependent. Studies in vivo have shown that hypertrophic cardiomyopathy is associated with a depression in cytochrome c oxidase (COX) activity, which could be involved in VEGF-mediated cellular function. The present study was undertaken to test the hypothesis that COX is a determinant factor in Cu-induced regression of cardiomyocyte hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylepherine (PE) at a final concentration of 100 microM in cultures for 48 h to induce cell hypertrophy. The hypertrophic cells were then treated with Cu sulfate at a final concentration of 5 microM in cultures for 24 h with a concomitant presence of PE to examine the effect of Cu on the regression of cardiomyocyte hypertrophy. Cell size changes were determined by flow cytometry, protein content, and molecular markers. Gene silencing was applied to study the effect of COX activity change on the regression of cardiomyocyte hypertrophy. PE treatment decreased COX activity in hypertrophic cardiomyocytes, and Cu addition restored the activity along with the regression of cell hypertrophy. Gene silencing using siRNA targeting COX-I significantly inhibited COX activity and blocked the Cu-induced regression of cell hypertrophy. VEGF alone also restored COX activity; but under the condition of COX inhibition by gene silencing, VEGF-induced regression of cell hypertrophy was suppressed. This study demonstrates that both Cu and VEGF can restore COX activity that is depressed in hypertrophic cardiomyocytes, and COX plays a determinant role in both Cu- and VEGF-induced regression of cardiomyocyte hypertrophy.

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“…These data support a role for androgen signaling in stress-responsive activation of eNOS, which is coupled to VEGF signaling. Since induction of VEGF by Gq stress, VEGF receptor expression, and androgen receptor expression are all reported in cardiac myocytes (32)(33)(34)(35)(36), androgen could mediate stress-responsive eNOS activation by enhancing VEGF signaling in cardiac myocytes as well. Future studies will be needed to elucidate the molecular mechanisms for stress activation of eNOS in males.…”

Section: Figurementioning

confidence: 99%

PDE5 inhibitor efficacy is estrogen dependent in female heart disease

Sasaki¹,

Nagayama²,

Blanton³

et al. 2014

J. Clin. Invest.

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Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.

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Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway

Abstract: Enhanced VEGFR-1 signalling is involved in Cu regression of cardiomyocyte hypertrophy, and the PKG-1 pathway is likely associated with VEGFR-1.

Cited by 52 publications

References 21 publications

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

Cytochrome c Oxidase is Essential for Copper-Induced Regression of Cardiomyocyte Hypertrophy

PDE5 inhibitor efficacy is estrogen dependent in female heart disease

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