Abstract 17047: SnoRNA33 as a New Therapeutic Target in Ischemia/Reperfusion Induced Myocardial Injury
Introduction: SnoRNA33 is a H/ACA RNA, which is predicted to guide the pseudouridylation of 28S rRNA U4966. Other than this information, roles and mechanisms of snoRA33 in human physiology and pathology are largely unknown. Our preliminary data showed that snoRNA33 expression was highly upregulated in mouse myocardial ischemic/reperfusion (I/R) injury. This study is intended to evaluate the utility of snoRNA33 as a new preventive and therapeutic target in I/R induced mouse myocardial injury and to investigate underlying cell and molecular mechanisms.
Hypothesis: We hypothesize that snoRNA33 may be a genetic risk factor and therapeutic target in CAD.
Methods: Male C57BL/6J mice, 8-12week-old, were subjected to either sham operation or myocardial I/R by a 40 min occlusion of the left anterior descending coronary artery followed by 3 h reperfusion without or with i.v. morpholino-snoRNA33 antisense oligo (MAO), or its scrambled control (MAOsc) either prior to or during the operation. 24 h later, mice were sacrificed and their hearts and sera were harvested for further analyses including assessing infarct size, assaying apoptosis and serum troponin-I levels. The mechanisms underlying the effect of snoRNA33 were also investigated in in vitro cell culture system by the TUNEL staining and RNA-seq analysis.
Results: The size of myocardial infarction/area at risk or myocardial apoptosis was significantly smaller or less severe in MAO mouse group than in MAOsc mouse group administered either prior to or during the operation. Serum tCTn1 levels were significantly lower in the MAO group than the MAOsc group (%cTn-1: 60±20 vs. 100±1.1, p <0.01, N=5/group). Overexpression of snoRNA33 augmented apoptosis while inhibition of snoRNA33 expression reduced staurosporine induced apoptosis in cultured mouse HL-1 cardiomyocytes. RNA-seq analysis revealed that out of 890 differentially expressed genes, Wnt/β-catenin signaling pathway was the top involved canonical pathway with 21 genes in the pathway downregulated in the MAO group vs MAOsc group.
Conclusions: Inhibition of SnoRNA 33 could attenuate IR induced myocardial injury preventively and therapeutically. SnoRNA33 is promising as a new therapeutic target in CAD.
Author Disclosures: S.Q. Ye: None. D. Heruth: None. M. Xiong: None. L.Q. Zhang: None.
- © 2016 by American Heart Association, Inc.