Deficiency of a novel gene, Yulink, predisposes to heart failure and ventricular arrhythmia

Heart failure is a major cardiovascular disease and is associated with significant morbidity and mortality. Sudden cardiac death (SCD) in heart failure is a disastrous cardiovascular phenomenon. However, few studies have examined the genetic background that determines susceptibility to heart failure and SCD. We found that deficiency of a newly identified gene, Yulink, promoted cardiac alternans in zebrafish cardiomyocytes, and genetic knockdown (KD) resulted in pericardial edema, decreased cardiac output, and premature ventricular contractions. Yulink KD morphants exhibited irregular action potentials, slower Ca2+ reuptake, and alternans of Ca2+ transients and action potential duration, which are hallmarks for SCD susceptibility in heart failure. Similarly, KD of Yulink in mouse cardiomyocytes disrupted Ca2+ reuptake, reduced the expression of cardiac Serca2, and resulted in a reduction in peroxisome proliferator-activated receptor (PPAR)γ activity. Expression of Serca2 was up-regulated by PPARγ agonists and down-regulated by PPARγ-short hairpin RNA KD, suggesting that Yulink regulates Serca2 expression through PPARγ. Finally, Yulink and Serca2 were down-regulated in ventricular samples of hearts from patients with heart failure due to dilated cardiomyopathy. Our results highlight the interaction of Yulink with PPARγ in regulating Serca2 expression and suggest a mechanistic role of the Yulink in the development of human heart failure and SCD.