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Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human

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 remai...

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Main Authors: Roh, Jason (Author) , Castro, Claire (Author) , Yu, Andy (Author) , Rana, Sarosh (Author) , Shahul, Sajid (Author) , Gray, Kathryn J. (Author) , Honigberg, Michael C. (Author) , Ricke-Hoch, Melanie (Author) , Iwamoto, Yoshiko (Author) , Yeri, Ashish (Author) , Kitchen, Robert (Author) , Guerra, Justin Baldovino (Author) , Hobson, Ryan (Author) , Chaudhari, Vinita (Author) , Chang, Bliss (Author) , Sarma, Amy (Author) , Lerchenmüller, Carolin (Author) , Al Sayed, Zeina R. (Author) , Diaz Verdugo, Carmen (Author) , Xia, Peng (Author) , Skarbianskis, Niv (Author) , Zeisel, Amit (Author) , Bauersachs, Johann (Author) , Kirkland, James L. (Author) , Karumanchi, S. Ananth (Author) , Gorcsan, John (Author) , Sugahara, Masataka (Author) , Damp, Julie (Author) , Hanley-Yanez, Karen (Author) , Ellinor, Patrick T. (Author) , Arany, Zoltan (Author) , McNamara, Dennis M. (Author) , Hilfiker-Kleiner, Denise (Author) , Rosenzweig, Anthony (Author)
Format: Article (Journal)
Language:English
Published: April 2024
In: Science translational medicine
Year: 2024, Volume: 16, Issue: 743, Pages: 1-14
ISSN:1946-6242
DOI:10.1126/scitranslmed.adi0077
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scitranslmed.adi0077
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/scitranslmed.adi0077
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Author Notes: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, for the IPAC Investigators, Denise Hilfiker-Kleiner, Anthony Rosenzweig
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Summary: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.
Item Description:Online veröffentlicht: 17. April 2024
Gesehen am 02.12.2024
Physical Description:Online Resource
ISSN:1946-6242
DOI:10.1126/scitranslmed.adi0077

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