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Cardiac-specific inactivation of Prdm16 effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes
Ist Teil von
American journal of physiology. Heart and circulatory physiology, 2020-04, Vol.318 (4), p.H764-H777
Ort / Verlag
United States: American Physiological Society
Erscheinungsjahr
2020
Quelle
MEDLINE
Beschreibungen/Notizen
A variant in the
locus has been correlated with QRS duration in an electrocardiogram genome-wide association study, and the deletion of
has been implicated as a causal factor of the dilated cardiomyopathy that is linked to 1p36 deletion syndrome. We aimed to determine how a null mutation of
affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific
conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific
knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay.
-null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR,
-null hearts upregulated extracellular matrix-related genes (
,
) and α-smooth muscle actin (
), a myofibroblast marker. Moreover, TGF-β signaling was activated in
-null hearts, as evidenced by increased
transcript levels and phosphorylated Smad2. However, the inhibition of TGF-β receptor did not reverse the aberrations in conduction in cardiac-specific
knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis,
-null hearts experienced dysregulated expression of ion channel genes, including
,
,
, and
. Mice with
-null hearts develop abnormalities in cardiac conduction and cardiomyopathy-associated phenotypes, including fibrosis and cellular hypertrophy. Further, the RNA-seq findings suggest that impairments in ion homeostasis (Ca
, K
, and Na
) may at least partially underlie the abnormal conduction in cardiac-specific
knockout mice.
This is the first study that describes aberrant cardiac function and cardiomyopathy-associated phenotypes in an appropriate murine genetic model with cardiomyocyte-specific
-null mutation. It is noteworthy that the correlation of
with QRS duration is replicated in a murine animal model and the potential underlying mechanism may be the impairment of ion homeostasis.