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CRISPR-Cas9 base editing to render CaMKIIδ phosphoresistant improves survival and cardiac function in heart failure

ABSTRACT: We ablated the autophosphorylation site of CaMKIIδ (T287) using CRISPR-Cas9 adenine base editing technology. Ten-weeks old C57Bl6 wildtype and CaMKIIδ T287A mice were subjected to either sham or severe transverse aortic constriction (sTAC) surgery (WT-Sham, WT-sTAC, T287A-Sham, T287A-sTAC; 3 biological replicates per group). Two weeks after the surgery, hearts were harvested for RNA isolation and subsequent bulk RNA sequencing and gene expression profiling analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE227720 | GEO | 2025/07/22

REPOSITORIES: GEO

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Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.

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CRISPR-Cas9 base editing to render CaMKIIδ phosphoresistant improves survival and cardiac function in heart failure

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