Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 425, S-41390 Gothenburg, Sweden.
Cardiovasc Res. 2014 Feb 1;101(2):229-35. doi: 10.1093/cvr/cvt260. Epub 2013 Nov 20.
Germ-line mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) pathway cause developmental disorders called RASopathies. Hypertrophic cardiomyopathy (HCM) is the most common myocardial pathology and a leading cause of death in RASopathy patients. KRAS mutations are found in Noonan and cardio-facio-cutaneous syndromes. KRAS mutations, unlike mutations of RAF1 and HRAS, are rarely associated with HCM. This has been attributed to the fact that germ-line KRAS mutations cause only a moderate up-regulation of the MAPK pathway. Highly bioactive KRAS mutations have been hypothesized to cause severe cardiomyopathy incompatible with life. The aim of this study was to define the impact of KRAS(G12D) expression in the heart.
To generate mice with endogenous cardiomyocyte-specific KRAS(G12D) expression (cKRAS(G12D) mice), we bred mice with a Cre-inducible allele expressing KRAS(G12D) from its endogenous promoter (Kras2(LSL)) to mice expressing Cre under control of the cardiomyocyte-specific α-myosin heavy chain promoter (αMHC-Cre). cKRAS(G12D) mice showed high levels of myocardial ERK and AKT signalling. However, surprisingly, cKRAS(G12D) mice were born in Mendelian ratios, appeared healthy, and had normal function, size, and histology of the heart.
Mice with cardiomyocyte-specific KRAS(G12D) expression do not develop heart pathology. These results challenge the view that the level of MAPK activation correlates with the severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes.
编码 RAS/丝裂原活化蛋白激酶（MAPK）途径组成部分的基因中的种系突变可导致称为 RAS 病的发育障碍。肥厚型心肌病（HCM）是最常见的心肌病理学，也是 RAS 病患者死亡的主要原因。KRAS 突变存在于 Noonan 和心面肢综合征中。与 RAF1 和 HRAS 的突变不同，KRAS 突变很少与 HCM 相关。这归因于种系 KRAS 突变仅导致 MAPK 途径的中度上调。据推测，高生物活性的 KRAS 突变会导致严重的心肌病，使其无法生存。本研究的目的是确定 KRAS(G12D)在心脏中的表达的影响。
为了生成具有内源性心肌细胞特异性 KRAS(G12D)表达的小鼠（cKRAS(G12D)小鼠），我们将表达 KRAS(G12D)的可诱导等位基因的小鼠（Kras2(LSL)）与在心肌细胞特异性α肌球蛋白重链启动子（αMHC-Cre）控制下表达 Cre 的小鼠进行杂交。cKRAS(G12D)小鼠表现出高水平的心肌 ERK 和 AKT 信号传导。然而，令人惊讶的是，cKRAS(G12D)小鼠以孟德尔比例出生，外观健康，心脏的功能、大小和组织学均正常。
具有心肌细胞特异性 KRAS(G12D)表达的小鼠不会发展为心脏病理学。这些结果挑战了 MAPK 激活水平与 RAS 病中 HCM 严重程度相关的观点，并表明 MAPK 独立的策略可能对这些综合征的新治疗方法的开发具有意义。
