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. 2014 Feb 1;101(2):229-35.
doi: 10.1093/cvr/cvt260. Epub 2013 Nov 20.

Myocardial KRAS(G12D) expression does not cause cardiomyopathy in mice

Martin G Dalin  1 , Zhiyuan Zou, Margareta Scharin-Täng, Roghaiyeh Safari, Christin Karlsson, Martin O Bergo
Affiliations

Myocardial KRAS(G12D) expression does not cause cardiomyopathy in mice

Martin G Dalin et al. Cardiovasc Res. .

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.

Keywords: Cardio-facio-cutaneous syndrome; Cardiomyopathy; KRAS; Noonan syndrome; RASopathies.

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