Yi Jae-Sung, Perla Sravan, Bennett Anton M
Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA.
Yale Center for Molecular and Systems Metabolism, Yale University, New Haven, CT, 06520, USA.
Cardiovasc Drugs Ther. 2023 Dec;37(6):1193-1204. doi: 10.1007/s10557-022-07324-0. Epub 2022 Feb 14.
The RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious and recurrent cause of mortality in RASopathy patients, it is critical to understand the pathological signaling mechanisms that drive the disease. Therapies for the treatment of HCM and other RASopathy-associated comorbidities have yet to be fully realized. Recent developments have shown promise for the use of repurposed antineoplastic drugs that target the RAS-MAPK pathway for the treatment of RASopathy-associated HCM. However, given the impact of the RAS-MAPK pathway in post-developmental physiology, establishing safety and evaluating risk when treating children will be paramount. As such insight provided by preclinical and clinical information will be critical. This review will highlight the cardiovascular manifestations caused by the RASopathies and will discuss the emerging therapies for treatment.
RAS/丝裂原活化蛋白激酶（MAPK）信号通路控制着众多发育及发育后过程。现在已经明确，RAS-MAPK信号通路中的突变会引发一系列发育性疾病，统称为RAS病。RAS病包括努南综合征、伴有多发雀斑的努南综合征、心面皮肤综合征、1型神经纤维瘤病和科斯特洛综合征。RAS病患者表现出广泛的先天性心脏缺陷（CHD），如瓣膜异常和肥厚型心肌病（HCM）。由于心血管缺陷是RAS病患者最严重且反复出现的死亡原因，了解驱动该疾病的病理信号传导机制至关重要。治疗HCM及其他与RAS病相关的合并症的疗法尚未完全实现。最近的进展表明，将靶向RAS-MAPK信号通路的抗肿瘤药物重新用于治疗与RAS病相关的HCM具有前景。然而，鉴于RAS-MAPK信号通路在发育后生理学中的影响，在治疗儿童时确定安全性并评估风险将至关重要。因此，临床前和临床信息提供的见解将至关重要。本综述将重点介绍RAS病引起的心血管表现，并讨论新兴的治疗方法。
