From the Department of Cardiology, Zhongnan Hospital of Wuhan University, Hubei, China (G.Z., Y.W.).
Division of Cardiology, Department of Internal Medicine (G.Z., X.W., X.B., C.L., X.L., T.G.G., Z.V.W.), University of Texas Southwestern Medical Center, Dallas.
Hypertension. 2019 Feb;73(2):390-398. doi: 10.1161/HYPERTENSIONAHA.118.12084.
The heart manifests hypertrophic growth in response to elevation of afterload pressure. Cardiac myocyte growth involves new protein synthesis and membrane expansion, of which a number of cellular quality control machineries are stimulated to maintain function and homeostasis. The unfolded protein response is potently induced during cardiac hypertrophy to enhance protein-folding capacity and eliminate terminally misfolded proteins. However, whether the unfolded protein response directly regulates cardiac myocyte growth remains to be fully determined. Here, we show that GRP78 (glucose-regulated protein of 78 kDa)-an endoplasmic reticulum-resident chaperone and a critical unfolded protein response regulator-is induced by cardiac hypertrophy. Importantly, overexpression of GRP78 in cardiomyocytes is sufficient to potentiate hypertrophic stimulus-triggered growth. At the in vivo level, TG (transgenic) hearts overexpressing GRP78 mount elevated hypertrophic growth in response to pressure overload. We went further to show that GRP78 increases GATA4 (GATA-binding protein 4) level, which may stimulate Anf (atrial natriuretic factor) expression and promote cardiac hypertrophic growth. Silencing of GATA4 in cultured neonatal rat ventricular myocytes significantly diminishes GRP78-mediated growth response. Our results, therefore, reveal that protein-folding chaperone GRP78 may directly enhance cardiomyocyte growth by stimulating cardiac-specific transcriptional factor GATA4.
心脏在应对后负荷压力升高时表现出肥厚生长。心肌细胞生长涉及新的蛋白质合成和膜扩张，其中许多细胞质量控制机制被刺激以维持功能和体内平衡。未折叠蛋白反应在心脏肥厚期间被强烈诱导，以增强蛋白质折叠能力并消除终末错误折叠的蛋白质。然而，未折叠蛋白反应是否直接调节心肌细胞生长仍有待充分确定。在这里，我们表明，GRP78（葡萄糖调节蛋白 78kDa）-内质网驻留伴侣和未折叠蛋白反应的关键调节剂-被心脏肥厚诱导。重要的是，心肌细胞中 GRP78 的过表达足以增强肥大刺激引发的生长。在体内水平，过表达 GRP78 的 TG（转基因）心脏对压力超负荷反应表现出升高的肥厚生长。我们进一步表明，GRP78 增加了 GATA4（GATA 结合蛋白 4）的水平，这可能刺激 Anf（心房利钠因子）的表达并促进心脏肥厚生长。在培养的新生大鼠心室肌细胞中沉默 GATA4 可显著减少 GRP78 介导的生长反应。因此，我们的结果表明，蛋白质折叠伴侣 GRP78 可能通过刺激心脏特异性转录因子 GATA4 直接增强心肌细胞生长。
