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