Temporal Profile of Circulating microRNAs after Global Hypoxia-Ischemia in Newborn Piglets

Garberg, Håvard Tetlie; Huun, Marianne Ullestad; Baumbusch, Lars Oliver; Åsegg-Atneosen, Monica; Solberg, Rønnaug; Saugstad, Ola Didrik

doi:10.1159/000449032

Cited by 23 publications

(22 citation statements)

References 28 publications

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“…33 Few studies to date have examined miR-374a in neonatal HIE. A piglet model reported temporal changes in expression after injury 39 and a 2017 clinical HIE study confirmed downregulation in umbilical cord blood in neonatal HIE. 40 This study also reported the downregulation of miR-181b in infants with moderate and severe HIE and compared the predictive ability of miR-181b with biochemical and clinical markers in HIE (Table 4).…”

Section: Discussionmentioning

confidence: 92%

Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy

et al. 2019

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IMPORTANCE Neonatal hypoxic-ischemic encephalopathy (HIE) remains a significant cause of neurologic disability. Identifying infants suitable for therapeutic hypothermia (TH) within a narrow therapeutic time is difficult. No single robust biochemical marker is available to clinicians. OBJECTIVE To assess the ability of a panel of candidate microRNA (miRNA) to evaluate the development and severity of encephalopathy following perinatal asphyxia (PA). DESIGN, SETTING, AND PARTICIPANTS This validation study included 2 cohorts. For the discovery cohort, full-term infants with PA were enrolled at birth to the Biomarkers in Hypoxic-Ischemic Encephalopathy (BiHiVE1) study (2009-2011) in Cork, Ireland. Encephalopathy grade was defined using early electroencephalogram and Sarnat score (n = 68). The BiHiVE1 cohort also enrolled healthy control infants (n = 22). For the validation cohort, the BiHiVE2 multicenter study (2013-2015), based in Cork, Ireland (7500 live births per annum), and Karolinska Huddinge, Sweden (4400 live births per annum), recruited infants with PA along with healthy control infants to validate findings from BiHiVE1 using identical recruitment criteria (n = 80). The experimental design was formulated prior to recruitment, and analysis was conducted from June 2016 to March 2017. MAIN OUTCOMES AND MEASURES Alterations in umbilical cord whole-blood miRNA expression. RESULTS From 170 neonates, 160 were included in the final analysis. The BiHiVE1 cohort included 87 infants (21 control infants, 39 infants with PA, and 27 infants with HIE), and BiHiVE2 included 73 infants (control [n = 22], PA [n = 26], and HIE [n = 25]). The BiHiVE1 and BiHiVE2 had a median age of 40 weeks (interquartile range [IQR], 39-41 weeks) and 40 weeks (IQR, 39-41 weeks), respectively, and included 56 boys and 31 girls and 45 boys and 28 girls, respectively. In BiHiVE1, 12 candidate miRNAs were identified, and 7 of these miRNAs were chosen for validation in BiHiVE2. The BiHiVE2 cohort showed consistent alteration of 3 miRNAs; miR-374a-5p was decreased in infants diagnosed as having HIE compared with healthy control infants (median relative quantification, 0.38; IQR, 0.17-0.77 vs 0.95; IQR, 0.68-1.19; P = .009), miR-376c-3p was decreased in infants with PA compared with healthy control infants (median, 0.42; IQR, 0.21-0.61 vs 0.90; IQR, 0.70-1.30; P = .004), and mir-181b-5p was decreased in infants eligible for TH (median, 0.27; IQR, 0.14-1.41) vs 1.18; IQR, 0.70-2.05; P = .02). CONCLUSIONS AND RELEVANCE Altered miRNA expression was detected in umbilical cord blood of neonates with PA and HIE. These miRNA could assist diagnostic markers for early detection of HIE and PA at birth.

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Section: Discussionmentioning

confidence: 92%

Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy

et al. 2019

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“…We acknowledge that not all miRNAs identified using our human cohort showed a change in HI piglets. Many clinical studies of miRNA alterations in HIE find our miRNAs of interest to be downregulated [ 5 , 56 ], while we and others have seen the opposite effect in animals [ 57 ]. It is unclear as to whether these are cross-species differences or whether it simply reflects the unpredictable nature and severity of HI in the clinical setting, as our porcine cohort received a uniform insult.…”

Section: Discussionmentioning

confidence: 99%

Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury

et al. 2020

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Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs—miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128—were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival. Electronic supplementary material The online version of this article (10.1007/s12035-020-02018-w) contains supplementary material, which is available to authorized users.

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“…The physiological variables exhibited no significant differences at baseline between the hypoxia versus sham-operated control groups, for the parameters weight, pO 2 , pCO 2 , lactate, or BE [ 40 , 42 ]. Applying the fluorescence method for cfDNA estimation, piglets exposed to hypoxia exhibited a mean cfDNA level of 36.8±27.6 ng/ml at baseline (start of hypoxia) and an evident peak of 61.5±54.9 ng/ml at the end of hypoxia ( Table 2 and Fig 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…A total of n = 55 newborn piglets were included in the study at an age of 12–36 hours and in good general condition. All newborn piglets were anesthetized, ventilated, and surgically prepared, as previously described in detail [ 40 – 42 ]. Briefly, after approximately one hour of stabilization the intervention groups (n = 32 and n = 12) were exposed to global hypoxia for approximately 30–60 minutes and followed for 9.5 hours ( Fig 1 ).…”

Section: Methodsmentioning

confidence: 99%

Temporal patterns of circulating cell-free DNA (cfDNA) in a newborn piglet model of perinatal asphyxia

et al. 2018

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Perinatal asphyxia is a severe medical condition resulting from oxygen deficiency (hypoxia) at the time of birth, causing worldwide approximately 680,000 newborn deaths every year. Better prediction of severity of damages including early biomarkers is highly demanded. Elevated levels of circulating cell-free DNA (cfDNA) in blood have been reported for a range of different diseases and conditions, including cancer and prematurity. The objective of this study was to validate methods for assessing cfDNA in blood and cerebrospinal fluid (CSF) and to explore temporal variations in a piglet model of neonatal hypoxia-reoxygenation. Different cfDNA extraction methods in combination with cfDNA detection systems were tested, including a fluorescent assay using SYBR Gold and a qRT-PCR-based technique. Newborn piglets (n = 55) were exposed to hypoxia-reoxygenation, hypoxia-reoxygenation and hypothermia, or were part of the sham-operated control group. Blood was sampled at baseline and at post-intervention, further at 30, 270, and 570 minutes after the end of hypoxia. Applying the fluorescent method, cfDNA concentration in piglets exposed to hypoxia (n = 32) increased from 36.8±27.6 ng/ml prior to hypoxia to a peak level of 61.5±54.9 ng/ml after the intervention and deceased to 32.3±19.1 ng/ml at 570 minutes of reoxygenation, whereas the group of sham-operated control animals (n = 11) revealed a balanced cfDNA profile. Animals exposed to hypoxia and additionally treated with hypothermia (n = 12) expressed a cfDNA concentration of 54.4±16.9 ng/ml at baseline, 39.2±26.9 ng/ml at the end of hypoxia, and of 41.1±34.2 ng/ml at 570 minutes post-intervention. Concentrations of cfDNA in the CSF of piglets exposed to hypoxia revealed at post-intervention higher levels in comparison to the controls. However, these observations were only tendencies and not significant. In a first methodological proof-of-principle study exploring cfDNA using a piglet model of hypoxia-reoxygenation variations in the temporal patterns suggest that cfDNA might be an early indicator for damages caused by perinatal asphyxia.

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Temporal Profile of Circulating microRNAs after Global Hypoxia-Ischemia in Newborn Piglets

Cited by 23 publications

References 28 publications

Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy

Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy

Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury

Temporal patterns of circulating cell-free DNA (cfDNA) in a newborn piglet model of perinatal asphyxia

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