HIF-1-mediated up-regulation of cardiotrophin-1 is involved in the survival response of cardiomyocytes to hypoxia

Robador, Pablo A.; José, Gorka San; Rodrı́guez, Cristina; Guadall, Anna; Moreno, María U.; Beaumont, Javier; Fortuño, Ana; Dı́ez, Javier; Martínez-González, José; Zalba, Guillermo

doi:10.1093/cvr/cvr202

Cited by 42 publications

(26 citation statements)

References 41 publications

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“…Ultrasound in combination with CMBs and shPHD2 yielded the strongest gene down-regulation, consistent with previous reports 5, 51. HIF-1 activates the transcription of genes whose protein products may inhibit apoptosis in response to hypoxia/ischemia, including EPO, Cardiotrophin-1 (CT-1) and VEGF 52, 53, 54. We believe that silencing PHD2 is able to inhibit cell apoptosis under OGD.…”

Section: Discussionsupporting

confidence: 90%

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Zhang¹,

Sun²,

Ren³

et al. 2017

Theranostics

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Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles.

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Section: Discussionsupporting

confidence: 90%

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Zhang¹,

Sun²,

Ren³

et al. 2017

Theranostics

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“…In the ES cell system CT-1 exerts its pro-cardiogenic effect not through induction of cell hypertrophy but presumably by stimulation of cardiac cell commitment in early and proliferation in later stages of differentiation [42]. Further data of ours and others demonstrated that the expression of CT-1 is increased under hypoxia [1,38], which occurs under conditions of cardiac infarction, when cardiac cells become necrotic and cardiac regeneration is required. In this respect it has been previously reported that elevated levels of CT-1 occur in patients with unstable angina [46], acute myocardial infarction [19,48] and heart failure [47].…”

Section: Introductionmentioning

confidence: 58%

Stimulation of cardiomyogenesis from mouse embryonic stem cells by nuclear translocation of cardiotrophin-1

Mascheck¹,

Sharifpanah²,

Tsang³

et al. 2015

International Journal of Cardiology

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“…CT-1 expression has been shown to be regulated by various transcription factors that are activated only under pathophysiological conditions, such as hypoxia [29, 30]. Both systemic and local levels of CT-1 might be increased as a result of not only an upregulated production, but also a potential reduction in its degradation.…”

Section: Potential Sources Of Cardiotrophin-1mentioning

confidence: 99%

Update on the Pathophysiological Activities of the Cardiac Molecule Cardiotrophin-1 in Obesity

Asrih

Mach

Quercioli

et al. 2013

Mediators of Inflammation

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Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that has been reported to exert a variety of activities also in other organs such as the liver, adipose tissue, and atherosclerotic arteries. CT-1 has been shown to induce these effects via binding to a transmembrane receptor, comprising the leukaemia inhibitory factor receptor (LIFRβ) subunit and the glycoprotein 130 (gp130, a common signal transducer). Both local and systemic concentrations of CT-1 have been shown to potentially play a critical role in obesity. For instance, CT-1 plasma concentrations have been shown to be increased in metabolic syndrome (a cluster disease including obesity) probably due to adipose tissue overexpression. Interestingly, treatment with exogenous CT-1 has been shown to improve lipid and glucose metabolism in animal models of obesity. These benefits might suggest a potential therapeutic role for CT-1. However, beyond its beneficial properties, CT-1 has been also shown to induce some adverse effects, such as cardiac hypertrophy and adipose tissue inflammation. Although scientific evidence is still needed, CT-1 might be considered as a potential example of damage/danger-associated molecular pattern (DAMP) in obesity-related cardiovascular diseases. In this narrative review, we aimed at discussing and updating evidence from basic research on the pathophysiological and potential therapeutic roles of CT-1 in obesity.

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HIF-1-mediated up-regulation of cardiotrophin-1 is involved in the survival response of cardiomyocytes to hypoxia

Abstract: Hypoxia increased CT-1 levels in cardiac cells (in vitro and in vivo) through a direct regulation of CTF1 promoter by HIF-1α. This CT-1 activation by hypoxia may protect cells from apoptosis, thus supporting a protective role for CT-1 as a survival factor for cardiomyocytes.

Cited by 42 publications

References 41 publications

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Stimulation of cardiomyogenesis from mouse embryonic stem cells by nuclear translocation of cardiotrophin-1

Update on the Pathophysiological Activities of the Cardiac Molecule Cardiotrophin-1 in Obesity

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