Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human
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Published:2024-04-17
Issue:743
Volume:16
Page:
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ISSN:1946-6234
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Container-title:Science Translational Medicine
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language:en
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Short-container-title:Sci. Transl. Med.
Author:
Roh Jason D.1ORCID, Castro Claire1ORCID, Yu Andy1, Rana Sarosh2ORCID, Shahul Sajid3ORCID, Gray Kathryn J.4ORCID, Honigberg Michael C.1ORCID, Ricke-Hoch Melanie5ORCID, Iwamoto Yoshiko6, Yeri Ashish1, Kitchen Robert1ORCID, Guerra Justin Baldovino17ORCID, Hobson Ryan1, Chaudhari Vinita1ORCID, Chang Bliss1ORCID, Sarma Amy1ORCID, Lerchenmüller Carolin89, Al Sayed Zeina R.10ORCID, Diaz Verdugo Carmen10ORCID, Xia Peng1ORCID, Skarbianskis Niv11, Zeisel Amit11ORCID, Bauersachs Johann5ORCID, Kirkland James L.12ORCID, Karumanchi S. Ananth13ORCID, Gorcsan John14ORCID, Sugahara Masataka15ORCID, Damp Julie16, Hanley-Yanez Karen17ORCID, Ellinor Patrick T.110ORCID, Arany Zoltan18ORCID, McNamara Dennis M.17ORCID, , Hilfiker-Kleiner Denise519, Rosenzweig Anthony17ORCID, 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.
Affiliation:
1. Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. 2. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago School of Medicine, Chicago, IL 60637, USA. 3. Department of Anesthesia and Critical Care, University of Chicago School of Medicine, Chicago, IL 60637, USA. 4. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98104, USA. 5. Department of Cardiology and Angiology, Hannover Medical School, Hannover 30625, Germany. 6. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. 7. Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. 8. Department of Cardiology, Angiology, and Pneumology, University of Heidelberg, Heidelberg 69120, Germany. 9. German Center for Heart and Cardiovascular Research (DZHK), Partner Site, Heidelberg/Mannheim, Heidelberg 69120, Germany. 10. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. 11. Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel. 12. Departments of Medicine and Physiology and Bioengineering, Mayo Clinic, Rochester, MN 55905, USA. 13. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. 14. Penn State College of Medicine, Hershey, PA 17033, USA. 15. Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan. 16. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. 17. Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. 18. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 19. Department of Cardiovascular Complications of Oncologic Therapies, Medical Faculty of the Philipps University Marburg, Marburg 35037, Germany.
Abstract
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.
Publisher
American Association for the Advancement of Science (AAAS)
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