GSE262123 Mechanisms Underlying Dilated Cardiomyopathy Associated with FKBP12 Deficiency

Contributors : Md Abul Hassan Samee ; Kevin S Ho ; Susan L HamiltonSeries Type : Expression profiling by high throughput sequencingOrganism :To define the role of the immunophilin FKBP12 in cardiac function, two conditional models of FKBP12 deficiency were created using Fkbp1a floxed (FL) mice expressing Cre+ recombinase under the control of different promoters ( α-myosin heavy chain, αMHC, and muscle creatine kinase, MCK) that differ in both developmental stage of expression (E9 versus E 13) and Cre+ expression levels. In adult mice FKBP12 was reduced by 96% and 86% in αMHC-Cre+- and MCK-Cre+-FKBP12 deficient mice, respectively, compared to FL mice. FL mice and mice hemizygous for the αMHC Cre+ recombinase only (to assess potential cytotoxic effects of the Cre+ recombinase) were used as controls. Of these four strains of mice, only the αMHC-Cre+-FKBP12 deficient mice developed an early-onset dilated cardiomyopathy (DCM) and displayed both increa sed cardiomyocyte sarcoplasmic reticulum Ca2+ leak and large elevations (assessed with RNAseq and western blots) in Ankyrin repeat domain 1 protein (ANKRD1), a negative regulator of cardiac gene expression in response to stress. These data suggest that an FKBP12 deficiency that begins during cardia c development and reduces FKBP12 below a critical level causes RyR2 mediated Ca2+ leak and ANKRD1 elevation, leading to cardiac structural remodeling and the development of DCM. This Ca2+ leak/ANKRD1 pathway may represent a common ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Source Type: research