Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

中文翻译：

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小鼠和人类围产期心肌病和先兆子痫的胎盘衰老病理生理学是相同的

围产期心肌病（PPCM）是一种与先兆子痫相关的妊娠诱发心力衰竭的特发性形式。妊娠晚期的循环因素被认为是导致这两种疾病的原因，这表明存在共同的潜在病理生理过程。然而，驱动这一过程的因素仍不清楚。利用血清蛋白质组学，我们发现衰老相关分泌表型（SASP）是与生物衰老相关的细胞衰老标志物，是患有 PPCM 或先兆子痫的年轻女性中上调程度最高的途径。先兆子痫女性的胎盘显示出多种衰老和组织老化放大的标志物，以及 28 种循环蛋白的基因表达总体增加，这些循环蛋白导致先兆子痫或 PPCM 患者血清样本中 SASP 通路富集。表达最高的胎盘 SASP 因子激活素 A 与先兆子痫或 PPCM 女性的心功能障碍或心力衰竭严重程度相关。在由心肌细胞特异性删除编码过氧化物酶体增殖物激活受体 γ 共激活因子-1α 的基因诱导的 PPCM 小鼠模型中，在产后早期用针对激活素 II 型受体的单克隆抗体抑制激活素 A 信号传导可改善心脏功能。此外，在妊娠晚期使用抗衰老化合物非瑟酮来减轻胎盘衰老，可以改善这些动物的心脏功能。这些发现将衰老生物学与妊娠期心脏功能障碍联系起来，有助于阐明妊娠期心血管疾病的发病机制。