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

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Research
• Developmental Biology

Background:

• RASopathies are developmental disorders caused by germ-line mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway.
• Hypertrophic cardiomyopathy (HCM) is a frequent and fatal complication in RASopathy patients.
• KRAS mutations, unlike other RAS pathway mutations, are rarely linked to HCM, possibly due to moderate MAPK pathway activation.

Purpose of the Study:

• To investigate the impact of KRAS(G12D) expression specifically in cardiomyocytes.
• To determine if highly bioactive KRAS mutations cause severe heart pathology in vivo.

Main Methods:

• Generated cardiomyocyte-specific KRAS(G12D) transgenic mice (cKRAS(G12D)) by crossing Kras2(LSL) and αMHC-Cre mice.
• Assessed myocardial signaling pathways (ERK, AKT) and cardiac function, size, and histology.

Main Results:

• cKRAS(G12D) mice exhibited elevated myocardial ERK and AKT signaling.
• Despite high MAPK activation, these mice were born normally and displayed no cardiac abnormalities.
• Normal heart function, size, and histology were observed in cKRAS(G12D) mice.

Conclusions:

• Cardiomyocyte-specific KRAS(G12D) expression does not induce heart pathology in mice.
• The severity of HCM in RASopathies may not directly correlate with the level of MAPK pathway activation.
• MAPK-independent therapeutic strategies warrant investigation for treating RASopathy-associated cardiomyopathies.