Abstract 17944: DAPIT Knockdown Induces Dilated Cardiomyopathy Phenotypes in Zebrafish

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Background: The pathogenesis of dilated cardiomyopathy (DCM) could be partially a result of adenosine triphosphate (ATP) dysregulation in the myocardium. Diabetes-associated protein in insulin-sensitive tissue (DAPIT) is encoded by the upregulated during skeletal muscle growth 5 (USMG5) gene, which plays a crucial role in energy production in mitochondrial ATP synthase. However, the role of DAPIT in myocardial function is unknown. We investigated whether DAPIT is associated with the pathogenesis of DCM.

Method and Results: By microarray analysis, we found that the relative expression levels of USMG5 tended to be positively correlated with those of natriuretic peptide precursor A in human failed myocardium. We disrupted endogenous z-usmg5 in zebrafish, using morpholino (MO) oligonucleotides and analyzed the cardiac morphology and function at 72 hours post fertilization. Compared with that in the control MO group (n=21), pericardial sac (60520±16872 μm2 vs. 32962±6295 μm2, p < 0.0001, Figure A) and atrial areas (11190±1370 μm2 vs. 9052±1361 μm2, p < 0.0001, Figure B) were larger and the ventricular fractional shortening was reduced (16.5±4.7% vs. 22.0±6.0%, p = 0.003, Figure C) in the z-usmg5 MO group (n=19). Co-injection of wild-type z-usmg5 mRNA with its MO resulted in reduction of pericardial sac and atrial areas and an improvement of ventricular fractional shortening compared with that in the z-usmg5 MO group. The expression levels of natriuretic peptides were upregulated in the z-usmg5 MO group compared with that in the control MO group. Further, microarray analysis revealed that genes in the calcium signaling pathway were downregulated in the z-usmg5 MO group compared with that in the control MO group (p < 0.0001).

Conclusions: DAPIT could play a crucial role in the pathogenesis of DCM and thus, could be a therapeutic target for heart failure.

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