| First Author | Nam JM | Year | 2020 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 318 |
| Issue | 4 | Pages | H764-H777 |
| PubMed ID | 32083975 | Mgi Jnum | J:291042 |
| Mgi Id | MGI:6436036 | Doi | 10.1152/ajpheart.00647.2019 |
| Citation | Nam JM, et al. (2020) Cardiac-specific inactivation of Prdm16 effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes. Am J Physiol Heart Circ Physiol 318(4):H764-H777 |
| abstractText | A variant in the PRDM16 locus has been correlated with QRS duration in an electrocardiogram genome-wide association study, and the deletion of PRDM16 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 Prdm16 affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific Prdm16 conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific Prdm16 knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay. Prdm16-null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR, Prdm16-null hearts upregulated extracellular matrix-related genes (Ctgf, Timp1) and alpha-smooth muscle actin (Acta2), a myofibroblast marker. Moreover, TGF-beta signaling was activated in Prdm16-null hearts, as evidenced by increased Tgfb1-3 transcript levels and phosphorylated Smad2. However, the inhibition of TGF-beta receptor did not reverse the aberrations in conduction in cardiac-specific Prdm16 knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis, Prdm16-null hearts experienced dysregulated expression of ion channel genes, including Kcne1, Scn5a, Cacna1h, and Cacna2d2. Mice with Prdm16-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(2+), K(+), and Na(+)) may at least partially underlie the abnormal conduction in cardiac-specific Prdm16 knockout mice.NEW & NOTEWORTHY This is the first study that describes aberrant cardiac function and cardiomyopathy-associated phenotypes in an appropriate murine genetic model with cardiomyocyte-specific Prdm16-null mutation. It is noteworthy that the correlation of PRDM16 with QRS duration is replicated in a murine animal model and the potential underlying mechanism may be the impairment of ion homeostasis. |
