1. Prof. Ilona Hromadnikova, Ph.D.
Third Faculty of Medicine
Institute for the Care of the Mother and Child
Charles University
Department of Molecular Biology
and Cell Pathology
Cardiovascular and cerebrovascular disease associated microRNAs are dysregulated in placental tissues affected with preeclampsia and intrauterine growth restriction
Prof. Ilona Hromadnikova, Ph.D.

2. Children born to pregnancies complicated with preeclampsia
 early, life time cardiovascular risk
intermediate and long-term consequences of placental insufficiency
Childhood obesity
Diabetes mellitus
Hypertension
Early implementation of primary prevention strategies
Libby et al. Pre-eclampsia and the later development of type 2 diabetes in mothers and their children: an intergenerational study from the Walker cohort. Diabetologia 2007; 50(3):
Davis et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systemic review. Pediatrics 2012; 129(6):e

3. regulation of gene expression
MicroRNA (miRNA)
- miRBase.org database up-to-date
Homo Sapiens 2588 microRNAs
- 1 microRNA → regulation of gene expression
from 1 to >1000 various genes
Small noncoding single strand
RNA molecules (18-25 nucleotides)
microRNA
function:
regulation of gene expression
Processed from hairpin-containing
primary transcripts (pri-miRNA)
microRNA
target mRNA
miRISC complex interacts with target mRNA
 microRNA   protein
 microRNA   protein

4. Cardio/cerebrovascular microRNAs Association with risk factors
Kong et al. Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetol 2011;48:61-69.
Raitoharju et al. miR-21, miR-210, miR-34a, and miR-146a/b are up regulated in human atherosclerotic plaques in the Tempere vascular study. Atherosclerosis 2011;219:
Poliseno et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006;108:

5. Cardio/cerebrovascular microRNAs Association with cardiovascular diseases
Fichtlscherer et al. Circulating miRNAs in patients with coronary artery disease. Circ Res. 2010; 107:
van Rooij et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA 2006;103:
Ikeda et al. Altered microRNA expression in human heart disease. Physiol Genomics 2007;31:

6. Cardio/cerebrovascular microRNAs Association with cerebrovascular diseases
Li et al. Circulating microRNAs:Potential and emerging biomarkers for diagnosis of cardiovascular and cerebrovascular diseases. Biomed Res Int 2015; doi: /2015/
Volny et al. microRNAs in cerebrovascular diseases. Adv Exp Med Biol 2015;888:
Jin et al. Circulating microRNA: a novel potential biomarker for early diagnosis of intracranial aneurysm rupture; a case control study. J Transl Med 2013;11:296.

7. 29 PE, 12 IUGR delivery  34th week
20 normal pregnancies
35 GH
ACOG guidelines
80 PE
34 mild PE
46 severe PE
29 PE, 12 IUGR delivery  34th week
51 PE, 24 IUGR delivery  34th week
23 PE with previous hypertension
57 PE without previous hypertension
< 10th percentile
35 IUGR
15 oligo/anhydramnions
20 euhydramnions
Hromadnikova et al. Cardiovascular and cerebrovascular disease associated microRNAs aew dysregulated in placental tissues affected withgestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 2015;10(9):e

8. 11 PE, 11 IUGR 13 PE, 19 IUGR 13 PE, 17 IUGR 1 PE, 3 IUGR
Doppler ultrasonography
11 PE, 11 IUGR
13 PE, 19 IUGR
PI a.c.m. PI
 95th percentile
a.umbilicalis
 5th percentile
Absent/reversed end-diastolic
velocity waveforms
13 PE, 17 IUGR
CPR
(centralization of fetal circulation)
1 PE, 3 IUGR
 5th percentile
Hromadnikova et al. Cardiovascular and cerebrovascular disease associated microRNAs aew dysregulated in placental tissues affected withgestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 2015;10(9):e

9. Up-regulation of miR-499a-5p common feature of GH, PE and IUGR

10. Down-regulation of miR-26a-5p, miR-103a-3p
and miR-145-5p in early PE
Hromadnikova et al. Cardiovascular and cerebrovascular disease associated microRNAs aew dysregulated in placental tissues affected withgestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 2015;10(9):e

11. Down-regulation of miR-145-5p, miR-122-5p, miR-125b-5p
and miR-195-5p in early IUGR
Hromadnikova et al. Cardiovascular and cerebrovascular disease associated microRNAs aew dysregulated in placental tissues affected withgestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 2015;10(9):e

12. Up-regulation of miR-1-3p in IUGR with abnormal pulsatility index (PI) in a. umbilicalis
Hromadnikova et al. Cardiovascular and cerebrovascular disease associated microRNAs aew dysregulated in placental tissues affected withgestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 2015;10(9):e

13. Trend to decreased expression of other 10 microRNAs in early IUGR (multiple comparison p0.017)
miR-26a-5p p=0.031
miR-103a-3p p=0.047
miR-16-5p p=0.018
miR-100-5p p=0.023
miR-126-3p p=0.033
miR-143-3p p=0.043
miR-199a-5p p=0.043
miR-221-3p p=0.042
miR-342-3p p=0.039
miR-574-3p p=0.042
Hromadnikova et al. Cardiovascular and cerebrovascular disease associated microRNAs aew dysregulated in placental tissues affected withgestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 2015;10(9):e

14. Number of §predicted and/or
Number of §predicted and/or *validated genes that are regulated by microRNAs aberrantly expressed in placental tissues derived from GH, PE and IUGR
microRNA
miRWalk*
miRDB§
miRTar§
miR-1-3p
494
419
846
miR-26a-5p
375
515
181
miR-103a-3p
400
433
273
miR-145-5p 46
495
104
miR-499a-5p 7
249 3
miR-16-5p
458
1088
1157
miR-100-5p
371 26
229
miR-122-5p
121
187
237
miR-125b-5p
393
476
340
miR-126-3p
409 2 32
miR-143-3p 37 20
miR-195-5p
374
1089 39
miR-199a-5p 29
334 24
miR-221-3p
416
316
253
miR-342-3p
360
274 83
miR-574-3p
358 16

15. GESTATIONAL HYPERTENSION
Association of dysregulated microRNAs with risk factors and cardio/cerebrovascular diseases
GESTATIONAL
HYPERTENSION

16. Association of dysregulated microRNAs with risk factors and cardio/cerebrovascular diseases
PREECLAMPSIA
EARLY PREECLAMPSIA

17. IUGR Association of dysregulated microRNAs with risk factors
and cardio/cerebrovascular diseases
IUGR
EARLY IUGR
significant results
trend results

18. Epigenetic changes induced by pregnancy-related complications (gestational hypertension, preeclampsia and fetal growth restriction) in placental tissue may cause later onset of cardiovascular and cerebrovascular diseases in offspring

19. Department of Molecular Biology
Institute for the Care of the Mother and Child
Assoc.Prof. Ladislav Krofta, M.D.
Lucie Hympanova, M.D.
Katarina Ivankova, M.D.
Department of Molecular Biology
and Cell Pathology
Third Faculty of Medicine
Katerina Kotlabova, MSc.
Lenka Dvorakova, MSc.
The work was supported by the Charles University research program PRVOUK P32 and Ministry of Health of the Czech Republic grant AZV A