TY - JOUR
T1 - Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human
AU - IPAC Investigators, Denise
AU - Roh, Jason D.
AU - Castro, Claire
AU - Yu, Andy Z.
AU - Rana, Sarosh
AU - Shahul, Sajid
AU - Gray, Kathryn J.
AU - Honigberg, Michael C.
AU - Ricke-Hoch, Melanie
AU - Iwamoto, Yoshiko
AU - Yeri, Ashish S.
AU - Kitchen, Robert
AU - Guerra, Justin Baldovino
AU - Hobson, Ryan
AU - Chaudhari, Vinita
AU - Chang, Bliss
AU - Sarma, Amy
AU - Lerchenmüller, Carolin
AU - Sayed, Zeina R.Al
AU - Verdugo, Carmen Diaz
AU - Xia, Peng
AU - Skarbianskis, Niv
AU - Zeisel, Amit
AU - Bauersachs, Johann
AU - Kirkland, James L.
AU - Karumanchi, S. Ananth
AU - Gorcsan, John
AU - Sugahara, Masataka
AU - Damp, Julie
AU - Hanley-Yanez, Karen
AU - Ellinor, Patrick T.
AU - Arany, Zoltan
AU - McNamara, Dennis M.
AU - Kleiner, Hilfiker
AU - Rosenzweig, Anthony
N1 - Publisher Copyright:
© 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.adi0077
DO - 10.1126/scitranslmed.adi0077
M3 - Article
C2 - 38630848
AN - SCOPUS:85190833585
SN - 1946-6234
VL - 16
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 743
M1 - eadi0077
ER -