β-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apoptosis through differential subcellular activation of ERK1/2 and Akt

Grisanti, Laurel A.; Talarico, Jennifer A; Carter, Rhonda L.; Yu, Justine; Repas, Ashley A.; Radcliffe, Scott; Tang, Hoang-ai; Makarewich, Catherine A.; Houser, Steven R.; Tilley, Douglas G.

doi:10.1016/j.yjmcc.2014.02.009

Cited by 41 publications

(49 citation statements)

References 86 publications

(94 reference statements)

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“…(Benter et al, 2004). Studies examining the injurious effects of ErbB1 or ErbB2 inhibition/deletion also support involvement of ROS generation, mitochondrial channels and PKC (Gordon et al, 2009), and modulation of caspase-3 and pro-and anti-apoptotic Bcl proteins and JNK activity (Grazette et al, 2004;Uetani et al, 2009;Grisanti et al, 2014). The precise roles of these mediators in cardiac protection awaits further analysis.…”

Section: Role In Adaptive Protection -Ischaemic Preconditioningmentioning

confidence: 86%

“…In cardiac cells, EGFR transactivation has been linked to angiotensin (Rakesh et al, 2010), muscarinic (Krieg et al, 2002;Krieg et al, 2004;Miao et al, 2015), endothelin (Kodama et al, 2002;Chen et al, 2006), opioid (Cao et al, 2005;Cohen et al, 2007;Forster et al, 2007;Zhang et al, 2015), bradykinin (Methner et al, 2009), adrenergic (Noma et al, 2007;Grisanti et al, 2014), adenosine (Williams-Pritchard et al, 2011), and sphoingosine-1 phosphate (S1P) (Hofmann et al, 2009) GPCRs, with transactivation via angiotensin II (Ang II) perhaps the most well studied. Several Gq-linked receptors (Ang II, ET-1, -ARs) may promote cardiac hypertrophy/remodelling, whereas transactivation by adenosine, opioid, bradykinin or muscarinic receptors may be protective, enhancing cell survival.…”

Section: Mechanisms Of Egfr Transactivationmentioning

confidence: 99%

“…Inhibition of this signalling path promoted myocyte apoptosis. A G protein-independent process of EGFR transactivation may also occur with some β-blockers (e.g., alprenolol, carvedilol) in non-cardiac models (Kim et al, 2008), with these agents also known to protect against acute or long-term effects of myocardial I-R. Grisanti et al (2014) more recently identified EGFR involvement in compartment-specific signalling responses to the -agonist isoproterenol.…”

Section: Role Of the Egfr In Gpcr-triggered Cardioprotectionmentioning

confidence: 99%

“…Evidence of EGFR involvement in responses to putative GPCR triggers of ischaemic preconditioning, including adenosine (Williams-Pritchard et al, 2011), opioid (Krieg et al, 2004;Cohen et al, 2007;Forster et al, 2007), bradykinin (Cohen et al, 2007;Methner et al, 2009), S1P (Hofmann et al, 2009) and -adrenergic receptors (Noma et al, 2007;Grisanti et al, 2014), indirectly supports EGFR involvement in this protective response. More specific analyses confirms an essential role for EGFR in preconditioning: chronic inhibition of EGFR with AG1478 attenuates ischaemic preconditioning by 50% or more (Benter et al, 2005a); and acute inhibition of EGFR, MMP or HB-EGF negates protection via preconditioning, though no effects were observed on intrinsic I-R tolerance (Williams-Pritchard et al, 2011).…”

Section: Role In Adaptive Protection -Ischaemic Preconditioningmentioning

confidence: 99%

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Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

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Section: Role In Adaptive Protection -Ischaemic Preconditioningmentioning

confidence: 86%

Section: Mechanisms Of Egfr Transactivationmentioning

confidence: 99%

Section: Role Of the Egfr In Gpcr-triggered Cardioprotectionmentioning

confidence: 99%

Section: Role In Adaptive Protection -Ischaemic Preconditioningmentioning

confidence: 99%

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Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

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“…In cardiomyocytes, Nur77 expression can be induced by ischemia/reperfusion injury, and translocation of Nur77 to the mitochondria mediates cardiomyocyte apoptosis in response to oxidative stress (19). Interestingly, a recent report demonstrated that the expression of Nur77 in the heart was rapidly induced in vivo following ␤-adrenergic stimulation (20,21). However, at this time, the exact functional significance of Nur77 in the heart remains unknown.…”

mentioning

confidence: 99%

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Yan

Zhu

Huang

et al. 2015

Molecular and Cellular Biology

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The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (␤-AR) activation. However, the functional significance of Nur77 in ␤-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time-and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the ␤-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure. Cardiac hypertrophy is an adaptive process in response to various physiological or pathological stimuli associated with neurohumoral activation, elevated wall stress, and changes in volume load (1). Although initially adaptive, persistent hypertrophy induced by pathological conditions like myocardial infarction and hypertension has detrimental consequences on the heart and eventually progresses to heart failure, a major cause of death and disability in the industrialized world (1). At cellular and molecular levels, cardiac hypertrophy is characterized by increased myocyte size, sarcomerogenesis, and reexpression of a set of fetal genes, such as the atrial natriuretic factor, B-type natriuretic peptide, and ␤-myosin heavy chain genes, which are coordinately controlled by a subset of hypertrophy-responsive transcription factors, including myocyte enhancer factor 2 (MEF2), nuclear factor of activated T cells (NFAT), and GATA4 (2, 3) (4). Depending on the upstream hypertrophic stimuli, these transcriptional regulators can be directly phosphorylated or dephosphorylated by protein kinases, such as mitogen-activated protein (MAP) kinase and protein kinases A and C, as well as the calcium-activated phosphatase calcineurin, to facilitate hypertrophic gene expression (5-9). Disruption and/or attenuation of the activities of these transcription factors could serve as a potential therapeutic approach in terms of inhibiting the hypertrophic responses in the heart (10-12).NR4A receptors are immediate early genes that are regulated by various ...

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Assessment of Tyrosine Kinase Inhibitors and Survival and Cardiovascular Outcomes of Patients With Non–Small Cell Lung Cancer in Taiwan

et al. 2023

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ImportanceTyrosine kinase inhibitors (TKIs) have been recognized as the standard treatment for patients with non–small cell lung cancers (NSCLCs) and epidermal growth factor receptor (EGFR) sequence variation. Although TKIs have been reported to cause cardiotoxicity, they are widely administered owing to the high prevalence of EGFR sequence variation in Taiwan.ObjectiveTo compare the outcomes of death and major adverse cardiac and cerebrovascular events among patients with NSCLC who use and do not use TKIs in a national cohort.Design, Setting, and ParticipantsUsing data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, patients treated for NSCLC from 2011 to 2018 were identified, and their outcomes were analyzed, including death and major adverse cardiac and cerebrovascular events (MACCEs; such as heart failure, acute myocardial infarction, and ischemic stroke) after adjusting for age, sex, cancer stage, comorbidities, anticancer therapies, and cardiovascular drugs. The median follow-up duration was 1.45 years. The analyses were performed from September 2022 to March 2023.ExposuresTKIs.Main Outcomes and MeasuresCox proportional hazards models were used to estimate death and MACCEs in patients treated with and without TKIs. Given that death may reduce the incidence of cardiovascular events, the competing risk method was used to calculate the MACCE risk after adjustment for all potential confounders.ResultsOverall, 24 129 patients treated with TKIs were matched with 24 129 patients who did not receive TKIs (24 215 [50.18%] were female; and the mean [SD] age was 66.93 [12.37] years). Compared with those not receiving TKIs, the TKI group presented with a significantly lower hazard ratio (HR) of all-cause death (adjusted HR, 0.76; 95% CI, 0.75-0.78; P &lt; .001), and the reason for death was primarily cancer. In contrast, the HR of MACCEs significantly increased (subdistribution HR, 1.22; 95% CI, 1.16-1.29; P &lt; .001) in the TKI group. Furthermore, afatinib use was associated with a significantly reduced risk of death among patients receiving various TKIs (adjusted HR, 0.90; 95% CI, 0.85-0.94; P &lt; .001) compared with those receiving erlotinib and gefitinib, although the outcomes of MACCEs were similar between the 2 groups.Conclusions and RelevanceIn this cohort study of patients with NSCLC, TKI use was associated with reduced HRs of cancer-related death but increased HRs of MACCEs. These findings suggest the importance of close monitoring of cardiovascular problems in individuals receiving TKIs.

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β-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apoptosis through differential subcellular activation of ERK1/2 and Akt

Cited by 41 publications

References 86 publications

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Assessment of Tyrosine Kinase Inhibitors and Survival and Cardiovascular Outcomes of Patients With Non–Small Cell Lung Cancer in Taiwan

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