MicroRNA-320a/b is a Therapeutic Target and Biomarker for Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease arising in the peripartum period. 16 kDa-prolactin (16K PRL) and its subproduct microRNA (miR)-146a-5p are candidate biomarkers for PPCM. However, we showed that miR-146a-5p is not well upregulated in the sera of PPCM patients. Here, we found that miR-320a/b were the most specific miRNAs that suppressed the expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK). We transfected neonatal rat cardiomyocytes with plasmids containing full-length prolactin (23K PRL) or 16K PRL in vitro. We found that 23K PRL, but not 16K PRL, upregulated PERK signaling, and hypoxia promoted this effect. During the perinatal period, cardiomyocyte-specific PERK homogenous knockout (CM-KO) mice showed PPCM phenotypes after consecutive deliveries. Downregulation of PERK or JAK/STAT signaling and upregulation of apoptosis were observed in CM-KO mouse hearts. These results demonstrated that interruption of 23K PRL-PERK interaction by miR-320a/b could be a therapeutic strategy for PPCM. Funding Statement: This study was supported by the Japan Society for the Promotion of Science KAKENHI grant number JP18K16756 and JP20K17210 (T.S.) and by the research grant from Public Trust Cardiovascular Research Fund (T.S.). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The institutional review board of National Cerebral and Cardiovascular Center in Osaka approved this study. Eligible women were enrolled after providing written informed consent. Animal Ethics Approval Statement: All experiments were approved by the University of Tokyo Ethics Committee for Animal Experiments and strictly adhered to the guidelines for animal experiments of the University of Tokyo.