Inhibition of miR-29c Protects the Brain in a Rat Model of Prolonged Hypothermic Circulatory Arrest Tianxiang Gu MD, PhD Department of Cardiac Surgery.

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Presentation transcript:

Inhibition of miR-29c Protects the Brain in a Rat Model of Prolonged Hypothermic Circulatory Arrest Tianxiang Gu MD, PhD Department of Cardiac Surgery First Hospital of China Medical University

DISCLOSURES  There is no conflict of interest for all authors.

INTRODUCTION Neurological deficit induced by deep hypothermia circulatory arrest (DHCA) remains a major complication. Neurological deficit induced by deep hypothermia circulatory arrest (DHCA) remains a major complication. Ischemia-reperfusion injury caused by circulation arrest contributes mainly to the neurological injury after DHCA. Ischemia-reperfusion injury caused by circulation arrest contributes mainly to the neurological injury after DHCA. Oxidative stress and apoptotic neuronal death signaling pathways are involved in the brain suffering from CPB and DHCA. Oxidative stress and apoptotic neuronal death signaling pathways are involved in the brain suffering from CPB and DHCA.

Peroxisome proliferator-activated receptor-c (PPARc) coactivator-1α (PGC-1α) is enriched in brain and is a potent stimulator of mitochondrial biogenesis and respiration. Peroxisome proliferator-activated receptor-c (PPARc) coactivator-1α (PGC-1α) is enriched in brain and is a potent stimulator of mitochondrial biogenesis and respiration. As an endogenous regulator of PGC-1α,miR-29c plays dramatic roles in the brain development and neurite outgrowth. As an endogenous regulator of PGC-1α, miR-29c plays dramatic roles in the brain development and neurite outgrowth. Journal of Cerebral Blood Flow & Metabolism (2011)31,

OBJECTIVES  We tried to explore the possible neuroprotections of using miRNA-29c as a regulator of PGC-1α in the brain after DHCA in the current study.

Animals: Sprague-Dawley rats; Lentivirus Vectors for AntagomiR-29c  Chemical modified antisense oligonucleotides of rat miR- 29c (antagomiR-29c) lentivirus gene transfer vectors were constructed by Genechem (Shanghai, China).  The recombinant lentivirus vector of antagomiR-29c and the control lentivirus vector without antagomiR-29c were prepared and tittered to 1×10 9 TU/mL (transfection unit). METHODS

AntagomiR-29c transfection in vivo  Lentivirus control vector transfection was performed by intracerebroventricular injection;  Intracerebroventricular injection: a puncture needle was implanted into the lateral ventricle, the solutions were injected over 1 minute.

CPB and DHCA The CPB circuit apparatus for rats: a venous reservoir, a venous reservoir, a peristaltic pump, a peristaltic pump, a custom-designed oxygenator. a custom-designed oxygenator.

 Cannulation: right carotid artery and jugular vein.  The tail artery was cannulated for blood pressure monitoring and blood sampling.  CPB was conducted at a flow rate of 160 to 180 mL/kg/min and was consecutively decreased by half during the cooling period.  Circulatory arrest was conducted for 60 minutes when the pericranial temperature was cooled to 18 ℃.  The rats were re-warmed to a pericranial temperature of 34 ℃ and then CPB was weaned.

Experimental protocol

Neurological assessment  Cognitive functions: Modified hole board test.

 Vestibulomotor function: Beam balance task.  The duration it remained on the beam was recorded (maximum = 60s).

Histologic examination  Hippocampus were stained with Hematoxylin-eosin (HE);  Normal neurons and death neurons were counted using a defined rectangular field area with magnification of 200×.

miR29-c 、 PGC-1α 、 caspase-3 and MDA expression  In a parallel series of experiments, rat brains were collected 2 hours after the surgical procedure from the four groups (n=4 per group). qRT-PCR: miR-29c Western Blot: PGC-1α and caspase-3 Western Blot: PGC-1α and caspase-3 MDA Assay Kit: MDA MDA Assay Kit: MDA

RESULTS Mortality and exclusion  A total of 37 rats were enrolled in the protocol for neurological assessment. Complete data were obtained in the remaining 32 rats (n=8, for each of the four groups).

Physiologic parameters

Neurological assessment P<0.01,vs sham group; P<0.01,vs sham group; # P<0.05,vs DHCA group. # P<0.05,vs DHCA group. Vestibulomotor function Vestibulomotor function.

* P<0.05,vs sham group; # P<0.05,vs DHCA group. Cognitive function

miR-29c expression in the hippocampus *P<0.05, vs DHCA group. MDA Measurement * P<0.05,vs sham group; # P<0.05,vs DHCA group.

Expression of PGC-1α Densitometric quantification of PGC-1α (folds to the sham group). * P<0.01, vs sham group; # P<0.01,vs DHCA group.

Expression of Caspase-3 Densitometric quantification of caspase-3 (folds to the sham group). * P<0.01, vs sham group; # P<0.01,vs DHCA group.

Histological examination ×40 ×200 ×400 ShamDHCADHCA+ control vector DHCA+ antagomiR-29c Coronal brain sections of the hippocampus and the cerebellar vermis stained with HE Pathological scores * P<0.05, vs DHCA group.

DISCUSSION Salient findings  Inhibition of miR-29c reduced the level of MDA and apoptosis and increased the expression of PGC-1α of the hippocampus after DHCA.  Pretreatment with antagomiR-29c improved the vestibulomotor and cognitive functions during the early postoperative period and attenuated histological injuries of the hippocampus.

miRNAs and neurological injury  miRNAs have become a novel target for cerebral protection against ischemia in recent days.  Important roles of miR-134, miR-30a and miR-592 in pathophysiological process of cerebral ischemia have been identified in different models. (Neuroscience 2014;277: Neurochem Res.2014;39: (Neuroscience 2014;277: Neurochem Res.2014;39: J Neurosci. 2014; 34: ) J Neurosci. 2014; 34: )  The current data showed that miRNA-29c was a negative mediator of cerebral protection against neurological injuries of DHCA. DISCUSSION

miR-29c and PGC-1α  PGC-1α is vital for neuron survival under condition of ischemia or hypoxia through a mitochondrial pathway.  The brain protective function of PGC-1α have been identified in collective studies. (Nature. 2008;451: Neuropharmacology.2010; 59: Neuroscience. 2014; 281: ) (Nature. 2008;451: Neuropharmacology.2010; 59: Neuroscience. 2014; 281: )  The current data indicated that the expression of PGC-1α in the hippocampus was markedly enhanced by inhibition of miRNA-29c.

Mechanism for the observed neuroprotection

CONCLUSION  Inhibition of miR-29c attenuates neurological injuries induced by prolonged DHCA through a PGC-1α pathway.  This is the first report indicated that regulation of miRNAs may be a novel therapeutic strategy for attenuation of neurological injuries after DHCA.

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