Department of Pharmacology, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Room 945A MERB, 3500 N. Broad St., Philadelphia, PA 19010, USA.
Department of Cell and Molecular Physiology, Loyola University Chicago, Chicago 60153, IL, USA.
Cardiovasc Res. 2022 Mar 25;118(5):1276-1288. doi: 10.1093/cvr/cvab149.
Epidermal growth factor receptor (EGFR) is essential to the development of multiple tissues and organs and is a target of cancer therapeutics. Due to the embryonic lethality of global EGFR deletion and conflicting reports of cardiac-overexpressed EGFR mutants, its specific impact on the adult heart, normally or in response to chronic stress, has not been established. Using complimentary genetic strategies to modulate cardiomyocyte-specific EGFR expression, we aim to define its role in the regulation of cardiac function and remodelling.
A floxed EGFR mouse model with α-myosin heavy chain-Cre-mediated cardiomyocyte-specific EGFR downregulation (CM-EGFR-KD mice) developed contractile dysfunction by 9 weeks of age, marked by impaired diastolic relaxation, as monitored via echocardiographic, haemodynamic, and isolated cardiomyocyte contractility analyses. This contractile defect was maintained over time without overt cardiac remodelling until 10 months of age, after which the mice ultimately developed severe heart failure and reduced lifespan. Acute downregulation of EGFR in adult floxed EGFR mice with adeno-associated virus 9 (AAV9)-encoded Cre with a cardiac troponin T promoter (AAV9-cTnT-Cre) recapitulated the CM-EGFR-KD phenotype, while AAV9-cTnT-EGFR treatment of adult CM-EGFR-KD mice rescued the phenotype. Notably, chronic administration of the β-adrenergic receptor agonist isoproterenol effectively and reversibly compensated for the contractile dysfunction in the absence of cardiomyocyte hypertrophy in CM-EGFR-KD mice. Mechanistically, EGFR downregulation reduced the expression of protein phosphatase 2A regulatory subunit Ppp2r3a/PR72, which was associated with decreased phosphorylation of phospholamban and Ca2+ clearance, and whose re-expression via AAV9-cTnT-PR72 rescued the CM-EGFR-KD phenotype.
Altogether, our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72 expression.
表皮生长因子受体（EGFR）对多种组织和器官的发育至关重要，是癌症治疗的靶点。由于全球 EGFR 缺失的胚胎致死性和心脏过表达 EGFR 突变体的相互矛盾的报告，其对正常或慢性应激下的成年心脏的具体影响尚未确定。本研究使用互补的遗传策略来调节心肌细胞特异性 EGFR 的表达，旨在确定其在调节心脏功能和重塑中的作用。
一种带有α-肌球蛋白重链-Cre 介导的心肌细胞特异性 EGFR 下调（CM-EGFR-KD 小鼠）的 floxed EGFR 小鼠模型，在 9 周龄时出现收缩功能障碍，表现为舒张功能障碍，通过超声心动图、血流动力学和分离的心肌细胞收缩性分析进行监测。这种收缩缺陷随着时间的推移保持不变，在 10 个月大时没有明显的心脏重塑，之后这些小鼠最终发展为严重的心力衰竭和寿命缩短。用携带心肌肌钙蛋白 T 启动子的腺相关病毒 9 (AAV9)-编码 Cre (AAV9-cTnT-Cre) 对成年 floxed EGFR 小鼠进行 EGFR 的急性下调，可重现 CM-EGFR-KD 表型，而 AAV9-cTnT-EGFR 治疗成年 CM-EGFR-KD 小鼠可挽救该表型。值得注意的是，β-肾上腺素能受体激动剂异丙肾上腺素的慢性给药可有效地、可逆地补偿 CM-EGFR-KD 小鼠的收缩功能障碍，而不会导致心肌细胞肥大。在机制上，EGFR 下调降低了蛋白磷酸酶 2A 调节亚基 Ppp2r3a/PR72 的表达，这与肌浆网磷蛋白和 Ca2+清除的磷酸化减少有关，通过 AAV9-cTnT-PR72 的表达可挽救 CM-EGFR-KD 表型。
总之，本研究强调了 EGFR 在正常生理条件下通过调节 PR72 表达来维持成年心脏收缩稳态中的先前未被认识的作用。
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