Abstract
Peripartum cardiomyopathy (PPCM) is a life-threatening heart failure occurring in the peripartum period. Although mal-angiogenesis, induced by the 16-kDa N-terminal prolactin fragment (16 K PRL), is involved in the pathogenesis, the effect of full-length prolactin (23 K PRL) is poorly understood. We transfected neonate rat cardiomyocytes with plasmids containing 23 K PRL or 16 K PRL in vitro and found that 23 K PRL, but not 16 K PRL, upregulated protein kinase RNA-like endoplasmic reticulum kinase (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. Moreover, in bromocriptine-treated CM-KO mice, cardiac function did not improve and cardiomyocyte apoptosis was not suppressed during the peripartum period. These results demonstrate that interaction between 23 K PRL and PERK signaling is cardioprotective during the peripartum term.
Highlights
PERK signaling is upregulated by 23 K PRL, but not 16 K PRL, in neonatal rat cardiomyocytes (NRCMs)
The expression of cleaved caspase 3, which is related to apoptosis, was increased in hypoxic NRCMs with 23 K PRL treatment compared to normoxic cells with or without the treatment
It is known that 23 K PRL protects against hypoxia[5] or inflammation-induced cell death[17] through AKT and STAT3 signaling
Summary
The expression of TNF was increased in CM-KO PP mice compared to CTRL PP mice (Fig. 2I). To further study PERK signaling activity, we performed western blotting analysis and observed increased phosphorylation of PERK, eIF2a, STAT3, and AKT in heart tissues of CTRL PP mice compared to CTRL NP mice (Fig. 3D). The levels of p-PERK were suppressed in CM-KO PP mice compared to CTRL PP mice (Fig. 3E). The expression of MMP-2, -3, and -9 in CTRL PP mice was the most upregulated among all groups (Fig. 3C).
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