scholarly journals The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

2020 ◽  
Vol 6 (16) ◽  
pp. eaax4826 ◽  
Author(s):  
Hai-Lian Bi ◽  
Xiao-Li Zhang ◽  
Yun-Long Zhang ◽  
Xin Xie ◽  
Yun-Long Xia ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Ubiquitin Proteasome System ◽  
Pathological Cardiac Hypertrophy ◽  
Epidermal Growth

Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1–treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy.

Mechanical stresses induce paracrine β-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor

2018 ◽  
Vol 132 (16) ◽  
pp. 1855-1874 ◽  
Author(s):  
Yang Li ◽  
Xiaoyi Zhang ◽  
Lu Li ◽  
Xiang Wang ◽  
Zhidan Chen ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cardiac Dysfunction ◽  
Cardiac Fibroblasts ◽  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Dependent Manner ◽  
Epidermal Growth ◽  
High Level

By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of β-2 microglobulin (β2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum β2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum β2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), β2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous β2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of β2M significantly reduced cardiac β2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of β2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from β2M-knockdown cardiomyocytes. In vivo, knockdown of β2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the β2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that β2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.

scholarly journals Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

2012 ◽  
Vol 30 (31) ◽  
pp. 3792-3799 ◽  
Author(s):  
Edward H. Romond ◽  
Jong-Hyeon Jeong ◽  
Priya Rastogi ◽  
Sandra M. Swain ◽  
Charles E. Geyer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cardiac Function ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
B 31 ◽  
Positive Breast Cancer

Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab.

scholarly journals Angiotensin II–Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense

Circulation ◽  
2002 ◽  
Vol 106 (8) ◽  
pp. 909-912 ◽  
Author(s):  
Shuntaro Kagiyama ◽  
Satoru Eguchi ◽  
Gerald D. Frank ◽  
Tadashi Inagami ◽  
Yuan Clare Zhang ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cardiac Hypertrophy ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Silencing of epidermal growth factor receptor reduces Na+/H+ exchanger 1 activity and hypertensive cardiac hypertrophy

2019 ◽  
Vol 170 ◽  
pp. 113667 ◽  
Author(s):  
María S. Brea ◽  
Romina G. Díaz ◽  
Daiana S. Escudero ◽  
Maite R. Zavala ◽  
Enrique L. Portiansky ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cardiac Hypertrophy ◽  
Growth Factor Receptor ◽  
Epidermal Growth
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