Epigenetic and senescence markers indicate an accelerated ageing-like state in women with preeclamptic pregnancies
Sonja Suvakov,
Ranine Ghamrawi,
Hajrunisa Cubro,
Haitao Tu,
Wendy M. White,
Yvonne S. Butler Tobah,
Natasa M. Milic,
Joseph P. Grande,
Julie M. Cunningham,
Fouad T. Chebib,
Larissa G.P. Langhi Prata,
Yi Zhu,
Tamara Tchkonia,
James L. Kirkland,
Karl A. Nath,
Aleksandar Milosavljevic,
Vesna D. Garovic
Affiliations
Sonja Suvakov
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Ranine Ghamrawi
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Hajrunisa Cubro
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Haitao Tu
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Division of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
Wendy M. White
Department of Obstetrics and Gynaecology, Mayo Clinic, Rochester, MN, USA
Yvonne S. Butler Tobah
Department of Obstetrics and Gynaecology, Mayo Clinic, Rochester, MN, USA
Natasa M. Milic
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Medical Statistics and Informatics, Medical Faculty, University of Belgrade, Serbia
Joseph P. Grande
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Julie M. Cunningham
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Fouad T. Chebib
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Larissa G.P. Langhi Prata
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
Yi Zhu
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
Tamara Tchkonia
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
James L. Kirkland
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA
Karl A. Nath
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Aleksandar Milosavljevic
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Vesna D. Garovic
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Obstetrics and Gynaecology, Mayo Clinic, Rochester, MN, USA; Corresponding author at: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Background: Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria and/or multisystem involvement. Disease-specific therapy has yet to be developed due to the lack of understanding of underlying mechanism(s). We postulate that accelerated ageing in general, and particularly cellular senescence, play a role in its pathophysiology. Methods: We compared women with preeclampsia vs. normotensive pregnancies with respect to epigenetic markers of ageing and markers of senescence in tissues/organs affected by preeclampsia (blood, urine, adipose tissue, and kidney). Findings: We demonstrate that preeclamptic compared to normotensive pregnant women: (i) undergo accelerated epigenetic ageing during pregnancy, as demonstrated by an “epigenetic clock”; (ii) exhibit higher levels/expression of senescence-associated secretory phenotype factors in blood and adipose tissue; (iii) display increased expression of p16INK4A in adipose tissue and renal sections, and (iv) demonstrate decreased levels of urinary α-Klotho (an anti-ageing protein) at the time of delivery. Finally, we provide data indicating that pre-treatment with dasatinib, a senolytic agent, rescues the angiogenic potential of mesenchymal stem cells (MSC) obtained from preeclamptic pregnancies, and promotes angiogenesis, even under pro-inflammatory conditions. Interpretation: Taken together, our results identify senescence as one of the mechanisms underpinning the pathophysiology of preeclampsia. Therapeutic strategies that target senescent cells may offer novel mechanism-based treatments for preeclampsia. Funding: This work was supported by NIH grants, R01 HL136348, R37 AG013925, P01 AG062413, R01 DK11916, generous gifts from the Connor Fund, Robert J. and Theresa W. Ryan and from The George G. Beasley family, the Noaber Foundation, and the Henry and Emma Meyer Professorship in Molecular Genetics.
