Myocardial KRASG12D expression does not cause cardiomyopathy in mice.

Cardiovascular Research

PubMedID: 24259500

Dalin MG, Zou Z, Scharin-Täng M, Safari R, Karlsson C, Bergo MO. Myocardial KRASG12D expression does not cause cardiomyopathy in mice. Cardiovasc Res. 2014;101(2):229-35.
Germline mutations in genes encoding components of the RAS/mitogen activated protein kinase 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 germline KRAS mutations cause only a moderate upregulation 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 a-myosin heavy chain promoter (aMHC-Cre). cKRAS(G12D) mice showed high levels of myocardial ERK and AKT signaling. However, surprisingly, h-KRAS(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 level of MAPK activation correlates with severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes.