LncRNA as a SERCA2a Inhibitor to Cause Intracellular Ca Overload and Contractile Dysfunction in a Mouse Model of Myocardial Infarction.

RATIONALE

Ca homeostasis-a critical determinant of cardiac contractile function-is critically regulated by SERCA2a (sarcoplasmic reticulum Ca-ATPase 2a). Our previous study has identified as a new lncRNA biomarker of acute myocardial infarction (MI).

OBJECTIVE

To evaluate the effects of on SERCA2a and the associated Ca homeostasis and cardiac contractile function in the setting of MI.

METHODS AND RESULTS

expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia. Knockdown of endogenous by virus-mediated silencing shRNA partially abrogated the ischemia-induced contractile dysfunction. Overexpression of in otherwise normal mice created similar impairment of cardiac function as that observed in MI mice. Moreover, at the cellular level, overexpression weakened the contractility of cardiac muscles. At the subcellular level, deleteriously altered the Ca transient leading to intracellular Ca overload in cardiomyocytes. At the molecular level, was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. The effects of were readily reversible on knockdown of this lncRNA. Notably, a sequence domain of gene that is conserved across species mimicked the effects of the full-length . Mutation of this domain or application of an antisense fragment to this conserved region efficiently canceled out the deleterious actions of . had no significant effects on other Ca-handling regulatory proteins.

CONCLUSIONS

is an endogenous SERCA2a inhibitor, acting by binding to SERCA2a protein to limit its intracellular level and inhibit its activity, and a contributor to the impairment of cardiac contractile function in MI. Therefore, anti- might be considered as a new therapeutic strategy for preserving SERCA2a activity and cardiac function under pathological conditions of the heart.