Novel <scp>EGFR</scp> inhibitors attenuate cardiac hypertrophy induced by angiotensin II

Peng, Kesong; Tian, Xin; Qian, Yuanyuan; Skibba, Melissa; Zou, Chunpeng; Liu, Zhiguo; Wang, Jingying; Xu, Zheng; Li, Xiaokun; Liang, Guang

doi:10.1111/jcmm.12763

Cited by 61 publications

(53 citation statements)

References 38 publications

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“…These data are consistent with increased EGFR signaling leads to pathological damage in DN patients [23]. We also found that AKT knockdown also inhibited TGF-β1 expression in renal mesangial SV40 cells, which is consistent with our previous observations in cardiomyocytes [9, 24] and kidney epithelial cells [25]. TGF-β1 is thought to be the core factor that contributes to the renal fibrosis of DN.…”

Section: Discussionsupporting

confidence: 92%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients. Endoplasmic reticulum (ER) stress caused by reactive oxygen species (ROS) is associated with DN progression. Epidermal growth factor receptor (EGFR) mediates oxidative stress and damage of cardiomyocytes in diabetic mice. Here we demonstrated that AG1478, a specific inhibitor of EGFR, blocked EGFR and AKT phosphorylation in diabetic mice. Oxidative stress and ER stress markers were eliminated after AG1478 administration. AG1478 decreased pro-fibrotic genes TGF-β and collagen IV. Furthermore, we found that high glucose (HG) induced oxidative stress and ER stress, and subsequently increased ATF4 and CHOP. These changes were eliminated by either AG1478 or ROS scavenger N-acetyl-L-cysteine (NAC) administration. These results were confirmed by knock-down approaches in renal mesangial SV40 cells. However, AG1478, not NAC, reversed HG induced EGFR and AKT phosphorylation. These results suggest that EGFR/AKT/ROS/ER stress signaling plays an essential role in DN development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases.

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Section: Discussionsupporting

confidence: 92%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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“…Our results show that the specific inhibition of cardiac EGFR is enough to avoid ERK1/2 activation by 1 nmol/L Ang II regardless of a potential contribution of ErbB4. These are similar results to those obtained by other authors in rats treated with Ang II and EGFR antisense oligonucleotides as well as in a recently published paper on H9c2 cells …”

Section: Discussionsupporting

confidence: 92%

“…However, activation of this receptor has also been associated with pathological conditions of the heart and vasculature, as well as with the development of diabetes and cancer . Systemic administration of PTKIs to prevent activation of cardiac EGFR can easily extend its action to other organs or even to other proteins such as ErbB4 . Furthermore, it has been reported that clinical use of PTKIs during cancer treatment leads to cardiac toxicity .…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Silencing Blunts the Slow Force Response to Myocardial Stretch

Brea

Díaz

Escudero

et al. 2016

JAHA

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BackgroundMyocardial stretch increases force biphasically: the Frank‐Starling mechanism followed by the slow force response (SFR). Based on pharmacological strategies, we proposed that epidermal growth factor (EGF) receptor (EGFR or ErbB1) activation is crucial for SFR development. Pharmacological inhibitors could block ErbB4, a member of the ErbB family present in the adult heart. We aimed to specifically test the role of EGFR activation after stretch, with an interference RNA incorporated into a lentiviral vector (small hairpin RNA [shRNA]‐EGFR).Methods and ResultsSilencing capability of p‐shEGFR was assessed in EGFR‐GFP transiently transfected HEK293T cells. Four weeks after lentivirus injection into the left ventricular wall of Wistar rats, shRNA‐EGFR–injected hearts showed ≈60% reduction of EGFR protein expression compared with shRNA‐SCR–injected hearts. ErbB2 and ErbB4 expression did not change. The SFR to stretch evaluated in isolated papillary muscles was ≈130% of initial rapid phase in the shRNA‐SCR group, while it was blunted in shRNA‐EGFR–expressing muscles. Angiotensin II (Ang II)‐dependent Na+/H+ exchanger 1 activation was indirectly evaluated by intracellular pH measurements in bicarbonate‐free medium, demonstrating an increase in shRNA‐SCR–injected myocardium, an effect not observed in the silenced group. Ang II‐ or EGF‐triggered reactive oxygen species production was significantly reduced in shRNA‐EGFR–injected hearts compared with that in the shRNA‐SCR group. Chronic lentivirus treatment affected neither the myocardial basal redox state (thiobarbituric acid reactive substances) nor NADPH oxidase activity or expression. Finally, Ang II or EGF triggered a redox‐sensitive pathway, leading to p90RSK activation in shRNA‐SCR‐injected myocardium, an effect that was absent in the shRNA‐EGFR group.ConclusionsOur results provide evidence that specific EGFR activation after myocardial stretch is a key factor in promoting the redox‐sensitive kinase activation pathway, leading to SFR development.

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“…EGFR was pharmacologically inhibited by two previously reported small-molecule inhibitors, AG1478 and 542 (Fig. 1A)17, or genetically silenced by siRNA in animal and cellular models. Inhibition of EGFR phosphorylation by AG1478 or 542 reduced myocardial inflammation, fibrosis, hypertrophy, apoptosis, and dysfunction in high fat diet-fed mice.…”

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confidence: 86%

EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice

Fang

Zhong

et al. 2016

Sci Rep

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Obesity is often associated with increased risk of cardiovascular diseases. Previous studies suggest that epidermal growth factor receptor (EGFR) antagonism may be effective for the treatment of angiotensin II-induced cardiac hypertrophy and diabetic cardiomyopathy. This study was performed to demonstrate if EGFR plays a role in the pathogenesis of hyperlipidemia/obesity-related cardiac injuries. The in vivo studies using both wild type (WT) and apolipoprotein E (ApoE) knockout mice fed with high fat diet (HFD) showed the beneficial effects of small-molecule EGFR inhibitors, AG1478 and 542, against obesity-induced myocardial injury. Administration of AG1478 and 542 significantly reduced myocardial inflammation, fibrosis, apoptosis, and dysfunction in both two obese mouse models. In vitro, EGFR signaling was blocked by either siRNA silencing or small-molecule EGFR inhibitors in palmitic acid (PA)-stimulated cardiomyocytes. EGFR inhibition attenuated PA-induced inflammatory response and apoptosis in H9C2 cells. Furthermore, we found that PA-induced EGFR activation was mediated by the upstream TLR4 and c-Src. This study has confirmed the detrimental effect of EGFR activation in the pathogenesis of obesity-induced cardiac inflammatory injuries in experimental mice, and has demonstrated the TLR4/c-Src-mediated mechanisms for PA-induced EGFR activation. Our data suggest that EGFR may be a therapeutic target for obesity-related cardiovascular diseases.

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Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II

Cited by 61 publications

References 38 publications

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Epidermal Growth Factor Receptor Silencing Blunts the Slow Force Response to Myocardial Stretch

EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice

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