Department of Medical of Sciences, Chosun University Graduate School, Gwangju 61452, Republic of Korea.
Department of Medical of Sciences, Chosun University Graduate School, Gwangju 61452, Republic of Korea; Cancer Mutation Research Center, Chosun University, Gwangju 61452, Republic of Korea.
Int J Cardiol. 2020 Jan 15;299:235-242. doi: 10.1016/j.ijcard.2019.07.049. Epub 2019 Jul 19.
Cardiac hypertrophy is associated with functional changes in cardiomyocytes, which often results in heart failure. The low-density lipoprotein receptor-related protein 1 (LRP1) is a large multifunctional endocytic receptor involved in many physiological and pathological processes. However, its function in the development of cardiac hypertrophy remains largely unclear.
Adenoviral constructs were used for either overexpression or silencing of LRP1 in both in vitro and in vivo experiments. Cardiac function was measured using the Millar catheter.
LRP1 expression was upregulated in both transverse aortic constriction (TAC)-induced hypertrophic myocardium and catecholamine (phenylephrine (PE) and norepinephrine (NE))- and angiotensin II (AngII)-induced hypertrophic cardiomyocytes. In addition, cell surface area, protein/DNA ratio, and the mRNA levels of hypertrophic markers were significantly increased in LRP1-overexpressing cardiomyocytes without catecholamine stimulation. Conversely, LRP1 inhibition by LRP1-specific siRNA or a specific ligand-binding antagonist (RAP) significantly rescued hypertrophic effects in PE, NE, or AngII-induced cardiomyocytes. LRP1 overexpression induced PKCα, then activated ERK, resulting in cardiac hypertrophy with the downregulation of SERCA2a and calcium accumulation, which was successfully restored in both LRP1-silenced cardiomyocytes and TAC-induced hearts.
LRP1 regulates cardiac hypertrophy via the PKCα-ERK dependent signaling pathway resulting in the alteration of intracellular calcium levels, demonstrating that LRP1 might be a potential therapeutic target for cardiac hypertrophy.
心肌肥厚与心肌细胞的功能变化有关，常导致心力衰竭。低密度脂蛋白受体相关蛋白 1（LRP1）是一种参与多种生理和病理过程的大型多功能内吞受体。然而，其在心肌肥厚发展中的作用在很大程度上仍不清楚。
在体外和体内实验中，使用腺病毒构建体过表达或沉默 LRP1。使用 Millar 导管测量心功能。
LRP1 在转主动脉缩窄（TAC）诱导的肥厚心肌和儿茶酚胺（苯肾上腺素（PE）和去甲肾上腺素（NE））以及血管紧张素 II（AngII）诱导的肥厚心肌细胞中均上调。此外，在没有儿茶酚胺刺激的情况下，LRP1 过表达的心肌细胞的细胞表面积、蛋白/DNA 比以及肥厚标志物的 mRNA 水平均显著增加。相反，LRP1 特异性 siRNA 或特异性配体结合拮抗剂（RAP）抑制 LRP1 可显著挽救 PE、NE 或 AngII 诱导的心肌细胞中的肥厚效应。LRP1 过表达诱导 PKCα，然后激活 ERK，导致心肌肥厚，SERCA2a 下调和钙积累，在 LRP1 沉默的心肌细胞和 TAC 诱导的心脏中均可成功恢复。
LRP1 通过 PKCα-ERK 依赖性信号通路调节心肌肥厚，导致细胞内钙水平的改变，表明 LRP1 可能是心肌肥厚的潜在治疗靶点。
