Long noncoding RNAs: emerging players in cardiac electrical and structural remodeling

OBJECTIVE Cardiac remodeling results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. METHODS We firstly performed the microarray profiling and bioinformatics analyses of long non-coding RNAs(lnc RNAs) in a mouse model of heart failure(HF) characterized by cardiac remodeling. Then we measured the levels of selected lnc RNAs with high profiles linking to cardiac dysfunction in clinical samples. RESULTS We found that circulating level of ZFAS1 was markedly lower in AMI than in non-AMI subjects. While CCRR is decreased in patients with HF.Then we identified ZFAS1 as an inhibitor of SERCA2 a by binding to SERCA2 a protein. Abnormally increased ZFAS1 in MI impaired cardiac function. Most prominently,we identified a conserved functional domain of ZFAS1,which is much shorter and responsible for its deleterious effects. Moreover, we found CCRR silencing induced arrhythmias by destruction of intercalated discs and gap junctions to slow longitudinal cardiac conduction in healthy mice. CCRR overexpression improves cardiac conduction by blocking endocytic trafficking of connexin43(Cx43) to prevent its degradation via binding to Cx43-interacting protein CIP85. We identified the functional domain of CCRR, which can reproduce the functional roles of full-length CCRR. CONCLUSION Our studies suggest ZFAS1 and CCRR play pivotal roles in cardiac remodeling, and provide therapeutic strategy for ameliorating cardiac dysfunction.