Reduced Maternal Circulating Cell‐Free Mitochondrial DNA Is Associated With the Development of Preeclampsia

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Zhengyang Zhou¹  Talisa Silzer²  Nicole R. Phillips²  Jie Sun²  Alexandra Blessing²  Sabrina M. Scroggins³  Mark K. Santillan³  Donna A. Santillan³  Jessica L. Bradshaw⁴  Contessa A. Ricci⁴  Styliani Goulopoulou⁴  Spencer C. Cushen⁴ 

[1]Department of Biostatistics and Epidemiology University of North Texas Health Science Center Fort Worth TX

[2]Department of Microbiology, Immunology and Genetics University of North Texas Health Science Center Fort Worth TX

[3]Department of Obstetrics and Gynecology University of Iowa Carver College of Medicine Iowa City IA

[4]Department of Physiology and Anatomy University of North Texas Health Science Center Fort Worth TX

关键词: cell‐free DNA;    DNase I;    mitochondrial DNA;    penalized regression analysis;    preeclampsia;   

DOI  :  10.1161/JAHA.121.021726

来源: DOAJ

【 摘 要 】

Background Circulating cell‐free mitochondrial DNA (ccf‐mtDNA) is a damage‐associated molecular pattern that reflects cell stress responses and tissue damage, but little is known about ccf‐mtDNA in preeclampsia. The main objectives of this study were to determine (1) absolute concentrations of ccf‐mtDNA in plasma and mitochondrial DNA content in peripheral blood mononuclear cells and (2) forms of ccf‐mtDNA transport in blood from women with preeclampsia and healthy controls. In addition, we sought to establish the association between aberrance in circulating DNA‐related metrics, including ccf‐mtDNA and DNA clearance mechanisms, and the clinical diagnosis of preeclampsia using bootstrapped penalized logistic regression. Methods and Results Absolute concentrations of ccf‐mtDNA were reduced in plasma from women with preeclampsia compared with healthy controls (P≤0.02), while mtDNA copy number in peripheral blood mononuclear cells did not differ between groups (P>0.05). While the pattern of reduced ccf‐mtDNA in patients with preeclampsia remained, DNA isolation from plasma using membrane lysis buffer resulted in 1000‐fold higher ccf‐mtDNA concentrations in the preeclampsia group (P=0.0014) and 430‐fold higher ccf‐mtDNA concentrations in the control group (P<0.0001). Plasma from women with preeclampsia did not induce greater Toll‐like receptor‐9–induced nuclear factor kappa‐light‐chain enhancer of activated B cells‐dependent responses in human embryonic kidney 293 cells overexpressing the human TLR‐9 gene (P>0.05). Penalized regression analysis showed that women with preeclampsia were more likely to have lower concentrations of ccf‐mtDNA as well as higher concentrations of nuclear DNA and DNase I compared with their matched controls. Conclusions Women with preeclampsia have aberrant circulating DNA dynamics, including reduced ccf‐mtDNA concentrations and DNA clearance mechanisms, compared with gestational age–matched healthy pregnant women.

【 授权许可】

Unknown