Supplemental Digital Content is available in the text. Pathological cardiac hypertrophy is one of the major predictors and inducers of heart failure, the end stage of various cardiovascular diseases. However, the molecular mechanisms underlying pathogenesis of pathological cardiac hypertrophy remain largely unknown. Here, we provided the first evidence that STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is a key negative regulator of this disease. We found that the expression of STEAP3 was reduced in pressure overload-induced hypertrophic hearts and phenylephrine-induced hypertrophic cardiomyocytes. In a transverse aortic constriction-triggered mouse cardiac hypertrophy model, STEAP3 deficiency remarkably deteriorated cardiac hypertrophy and fibrosis, whereas the opposite phenotype was observed in the cardiomyocyte-specific STEAP3 overexpressing mice. Accordingly, STEAP3 significantly mitigated phenylephrine-induced cell enlargement in primary neonatal rat cardiomyocytes. Mechanistically, via RNA-seq and immunoprecipitation-mass screening, we demonstrated that STEAP3 directly bond to Rho family small GTPase 1 and suppressed the activation of downstream mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade. Remarkably, the antihypertrophic effect of STEAP3 was largely blocked by overexpression of constitutively active mutant Rac1 (G12V). Our study indicates that STEAP3 serves as a novel negative regulator of pathological cardiac hypertrophy by blocking the activation of the Rac1-dependent signaling cascade and may contribute to exploring effective therapeutic strategies of pathological cardiac hypertrophy treatment.

中文翻译：

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STEAP3（前列腺 3 六跨膜上皮抗原）抑制病理性心脏肥大

补充数字内容在文本中可用。病理性心脏肥大是心力衰竭的主要预测因素和诱发因素之一，心力衰竭是各种心血管疾病的终末阶段。然而，病理性心脏肥大发病机制的分子机制在很大程度上仍然未知。在这里，我们提供了第一个证据，表明 STEAP3（前列腺 3 的六跨膜上皮抗原）是这种疾病的关键负调节因子。我们发现STEAP3在压力超负荷诱导的肥大心脏和去氧肾上腺素诱导的肥大心肌细胞中的表达降低。在横向主动脉缩窄触发的小鼠心脏肥大模型中，STEAP3 缺乏显着恶化了心脏肥大和纤维化，而在心肌细胞特异性 STEAP3 过表达小鼠中观察到相反的表型。因此，STEAP3 显着减轻了原代新生大鼠心肌细胞中苯肾上腺素诱导的细胞增大。从机制上讲，通过 RNA-seq 和免疫沉淀质量筛选，我们证明 STEAP3 直接与 Rho 家族小 GTPase 1 结合并抑制下游丝裂原活化蛋白激酶 - 细胞外信号调节激酶信号级联反应的激活。值得注意的是，STEAP3 的抗肥大作用在很大程度上被组成型活性突变体 Rac1 (G12V) 的过度表达所阻断。