Establishment and functional studies of a model of cardiomyopathy with cardiomyocyte-specific conditional knockout of Arhgef18.

Abstract

The rising incidence of cardiomyopathies poses a significant threat to the physical and mental health of patients. The establishment of an animal model that accurately reflects the clinicopathological characteristics of cardiomyopathy is essential for investigating its pathogenesis. In this study, a cardiomyocyte-specific Arhgef18 conditional knockout (cKO) mouse model was established with Cre/LoxP technology, and the results confirmed that the protein encoded by Arhgef18 (Rho/Rac guanine nucleotide exchange factor 18) was knocked out effectively in the myocardium of Arhgef18flox/flox; Nkx2.5-Cre (Arhgef18fl/fl cKO) mice. Compared to Arhgef18fl/fl mice, Arhgef18fl/fl cKO mice presented with slower body weight growth and no differences in survival curves. Cardiac structure and function revealed that Arhgef18fl/fl cKO mice developed biventricular enlargement, ventricular wall thinning and left-ventricular systolic dysfunction, along with increased Nppa and Nppb mRNA expression levels. Additionally, Arhgef18fl/fl cKO mice showed cardiomyocyte cytoskeletal rearrangements and cell polarity disorders. Our study results suggest that Arhgef18 cKO mice could provide an ideal animal model for the genetic investigation of cardiomyopathy.