Role of copper in regression of cardiac hypertrophy

Zheng, Lily; Han, Ping; Liu, Jiaming; Li, Rui; Yin, Weiqiang; Wang, Tao; Zhang, Wenjing; Kang, Yu

doi:10.1016/j.pharmthera.2014.11.014

Cited by 61 publications

(42 citation statements)

References 306 publications

(345 reference statements)

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“…33 , 34 VEGFR-2 is a critical factor in hypertrophic growth of cardiomyocytes. 35 , 36 We found that pioglitazone directly targeted VEGFR-2 and inhibited phospho-VEGFR-2 expression, suggesting that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy in neonatal rats by inhibiting VEGFR-2 signaling. Downstream PI3K/Akt signaling pathway also participates in survival and hypertrophy of these cells by inhibiting P53-dependent pathways and activating mTOR-dependent pathways, respectively.…”

Section: Discussionmentioning

confidence: 75%

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway

Zhong

Wen

et al. 2018

Arquivos Brasileiros De Cardiologia

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BackgroundPioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial.ObjectivesIn this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway.MethodsCardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups.ResultsPioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy.ConclusionsThese findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.

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Section: Discussionmentioning

confidence: 75%

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway

Zhong

Wen

et al. 2018

Arquivos Brasileiros De Cardiologia

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“…Recent studies have shown that Cu (II) containing compounds have a therapeutic potential in inflammation, cancer, cardiac hypertrophy, PD and other neurodegenerative disorders 14,43–45 , suggesting that Cu (II) ATSM may additionally exhibit cardioprotective properties. Studies where Cu (II) ATSM has been orally administered in rodent models of ALS and PD have reported improved neurological outcomes and increased survival through the reduction of oxidative stress 13–15,44 .…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

Srivastava

Blower

Aubdool

et al. 2016

Sci Rep

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Cu(II)ATSM was developed as a hypoxia sensitive positron emission tomography agent. Recent reports have highlighted the neuroprotective properties of Cu(II)ATSM, yet there are no reports that it confers cardioprotection. We demonstrate that Cu(II)ATSM activates the redox-sensitive transcription factor Nrf2 in human coronary artery smooth muscle cells (HCASMC) and cardiac myocytes (HCM), leading to upregulation of antioxidant defense enzymes. Oral delivery of Cu(II)ATSM in mice induced expression of the Nrf2-regulated enzymes in the heart and aorta. In HCASMC, Cu(II)ATSM increased expression of the Nrf2 stabilizer DJ-1, and knockdown of Nrf2 or DJ-1 attenuated Cu(II)ATSM-mediated heme oxygenase-1 and NADPH quinone oxidoreductase-1 induction. Pre-treatment of HCASMC with Cu(II)ATSM protected against the pro-oxidant effects of angiotensin II (Ang II) by attenuating superoxide generation, apoptosis, proliferation and increases in intracellular calcium. Notably, Cu(II)ATSM-mediated protection against Ang II-induced HCASMC apoptosis was diminished by Nrf2 knockdown. Acute treatment with Cu(II)ATSM enhanced the association of DJ-1 with superoxide dismutase-1 (SOD1), paralleled by significant increases in intracellular Cu(II) levels and SOD1 activity. We describe a novel mechanism by which Cu(II)ATSM induces Nrf2-regulated antioxidant enzymes and protects against Ang II-mediated HCASMC dysfunction via activation of the Nrf2/DJ-1 axis. Cu(II)ATSM may provide a therapeutic strategy for cardioprotection via upregulation of antioxidant defenses.

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“…Although it remains unclear whether the heart is damaged by lack of Cu, the evidence gained from animal models suggests that Cu supplementation may be beneficial. 19,20 …”

Section: Discussionmentioning

confidence: 99%

Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients With Friedreich Ataxia

Kruger

Yang

Parsons

et al. 2016

The American Journal of Cardiology

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Cardiomyopathy is a frequent cause of death in patients with Friedreich ataxia (FA), and a characteristic pathological feature is the focal accumulation of iron (Fe) in cardiomyocytes. This restricted localization of the metal contrasts with the diffuse cardiac Fe overload in hemochromatosis and transfusion siderosis. Nevertheless, heart Fe in FA contributes to cardiomyocyte necrosis, inflammation, and scarring as the disease progresses. A putative mechanism of cardiomyopathy in FA is Fe-mediated oxidative damage. Two other transition metals zinc (Zn) and copper (Cu), are diffusely distributed throughout normal hearts and the hearts of patients with FA. The myocardium in FA is also prone to deposits of calcium in the form of scattered concretions. In this study, heart tissues (left and right ventricular walls and ventricular septum) of 23 patients with genetically confirmed FA and 8 normal controls were obtained at autopsy and analyzed for Fe, Zn, Cu, and calcium. The principal assay methods were inductively coupled plasma optical emission spectrometry and plasma mass spectrometry. Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA. In conclusion, the decrease of Cu may be important in consideration of the potential benefit of Cu supplements in FA cardiomyopathy.

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Role of copper in regression of cardiac hypertrophy

Cited by 61 publications

References 306 publications

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway

Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway

Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients With Friedreich Ataxia

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