Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human
Authors: Roh Jason D. , Castro Claire , Yu Andy , Rana Sarosh , Shahul Sajid , Gray Kathryn J. , Honigberg Michael C. , Ricke-Hoch Melanie , Iwamoto Yoshiko , Yeri Ashish , Kitchen Robert , Guerra Justin Baldovino , Hobson Ryan , Chaudhari Vinita , Chang Bliss , Sarma Amy , Lerchenmüller Carolin , Al Sayed Zeina R. , Diaz Verdugo Carmen , Xia Peng , Skarbianskis Niv , Zeisel Amit , Bauersachs Johann , Kirkland James L. , Karumanchi S. Ananth , Gorcsan John , Sugahara Masataka , Damp Julie , Hanley-Yanez Karen , Ellinor Patrick T. , Arany Zoltan , McNamara Dennis M. ,   for the IPAC Investigators, Hilfiker-Kleiner Denise , Rosenzweig Anthony , Fett James D. , Pisarcik Jessica , McTiernan Charles , Schelbert Erik , Alharethi Rami , Rasmusson Kismet , Brunisholz Kim , Butler Amy , Budge Deborah , Kfoury A. G. , Horne Benjamin , Tuinei Joe , Brown Heather , Naftilan Allen J. , Russell Jill , Freehardt Darla , Hsich Eileen , Oblak Cynthia , Ewald Greg , Whitehead Donna , Flanagan Jean , Platts Anne , Elkayam Uri , Caro Jorge , Mullin Stephanie , Givertz Michael M. , Anello M. Susan , Rajagopalan Navin , Booth David , Sandlin Tiffany , Wijesiri Wendy , Cooper Leslie T. , Blauwet Lori A. , Brunner Joann , Phelps Mary , Kempf Ruth , Modi Kalgi , Norwood Tracy , Briller Joan , Griza Decebal Sorin , Felker G. Michael , Kociol Robb , Adams Patricia , Wells Gretchen , Thohan Vinay , Wesley-Farrington Deborah , Soots Sandra , Sheppard Richard , Michel Caroline , Lapointe Nathalie , Nathaniel Heather , Kealey Angela , Semigran Marc , Daher Maureen , Boehmer John , Silber David , Popjes Eric , Frey Patricia , Nicklas Todd , Alexis Jeffrey , Caufield Lori , Thornton John W. , Gentry Mindy , Robinson Vincent J. B. , Sharma Gyanendra K. , Holloway Joan , Powell Maria , Markham David , Drazner Mark , Fernandez Lynn , Zucker Mark , Baran David A. , Gimovsky Martin L. , Hochbaum Natalia , Patel Bharati , Adams Laura , Ramani Gautam , Gottlieb Stephen , Robinson Shawn , Fisher Stacy , Marshall Joanne , Haythe Jennifer , Mancini Donna , Bijou Rachel , Farr Maryjane , Marks Marybeth , Arango Henry , Bozkurt Biykem , Bolos Mariana , Mather Paul , Rubin Sharon , Bonita Raphael , Eberwine Susan , Skopicki Hal , Stergiopoulos Kathleen , McCathy-Santoro Ellen , Intravaia Jennifer , Maas Elizabeth , Safirstein Jordan , Kleet Audrey , Martinez Nancy , Corpoin Christine , Hesari Donna , Chaparro Sandra , Hudson Laura J. , Ghali Jalal K. , Injic Zora , Wittstein Ilan S. 
Published: April 2024

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.