The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure.

中文翻译：

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与 Ras 信号相关的分子作为心脏病的治疗靶点

Ras 家族的小鸟苷三磷酸 (GTP) 结合蛋白 (G 蛋白) 是正常心脏生长所需的细胞内信号转导的主要成分之一，但也与心脏肥大和心力衰竭的发展密切相关。本综述更新了 H-、K- 和 N-Ras 基因及其相关通路在心脏病中的作用。我们专注于心脏肥大和心力衰竭，其中 Ras 被研究得最多。我们还回顾了其他心脏疾病，如与 Ras 相关的遗传疾病。审查范围从基本概念扩展到治疗应用。尽管三个 Ras 基因具有几乎相同的一级结构，但它们之间存在重要的功能差异：H-Ras 主要调节心肌细胞大小，而 K-Ras 调节心肌细胞增殖。N-Ras 在心脏细胞中的研究最少，与心脏缺陷的相关性较小。临床上，致癌性 H-Ras 会导致 Costello 综合征和面皮肤骨骼综合征伴肥厚型心肌病和心律失常。另一方面，致癌 K-Ras 和 Ras-丝裂素活化蛋白激酶 (MAPK) 途径的其他基因的改变，如 Raf，会导致 Noonan 综合征和以心脏肥大和间隔缺损为特征的心面皮肤综合征。我们进一步回顾了 Ras 对心肌细胞中关键信号通路的调节，包括：(i) 经典的 Ras-Raf-MAPK 通路，导致更生理形式的心脏肥大；以及与病理性心脏肥大相关的其他途径，像 (ii) SAPK（应激激活蛋白激酶）途径 p38 和 JNK；(iii) 替代途径 Raf-钙调神经磷酸酶-活化 T 细胞核因子 (NFAT)。Ras 同种型或 Ras-MAPK 通路中基因的遗传改变导致 Ras 病，这些病症通常与心脏肥大或其他心脏病中的室间隔缺损有关。几项研究强调了 H-和 K-Ras 作为生理和病理性心脏肥大之间的枢纽的潜在作用，以及作为心脏肥大和衰竭的潜在治疗靶点。常与心脏肥大或室间隔缺损以及其他心脏疾病相关的病症。几项研究强调了 H-和 K-Ras 作为生理和病理性心脏肥大之间的枢纽的潜在作用，以及作为心脏肥大和衰竭的潜在治疗靶点。常与心脏肥大或室间隔缺损以及其他心脏疾病相关的病症。几项研究强调了 H-和 K-Ras 作为生理和病理性心脏肥大之间的枢纽的潜在作用，以及作为心脏肥大和衰竭的潜在治疗靶点。