Published on Aug. 1, 2019 in Cardiovasc Res volume 115(10).

PubMed ID: 30544252

DOI: 5244092

Abstract:

AIMS: We have shown that 14q32 microRNAs are highly involved in vascular remodellingand cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' smallnucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for14q32 snoRNAs in human cardiovascular disease. METHODS AND RESULTS: We performed alookup of the 14q32 region within the dataset of a genome wide association scan in5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk(PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster weresignificantly associated with heart failure. These snoRNA-cluster SNPs were notlinked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modifythe risk of cardiovascular disease independently. We looked at expression of 14q32snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronarybypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasmasamples drawn from patients with ST-elevation myocardial infarction directly afterhospitalization compared with 30 days after start of treatment. However, fittingwith the genomic associations, 14q32 snoRNA expression was highest in failing humanhearts. In vitro studies show that the 14q32 snoRNAs bind predominantly tomethyl-transferase Fibrillarin, indicating that they act through canonicalmechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seedsequences were highly conserved between humans and mice. CONCLUSION: 14q32 snoRNAsappear to play an independent role in cardiovascular pathology. 14q32 snoRNAs arespecifically regulated throughout the human vasculature and their expression isup-regulated during cardiovascular disease. Our data demonstrate that snoRNAs meritincreased effort and attention in future basic and clinical cardiovascular research.CI - Published on behalf of the European Society of Cardiology. All rights reserved. ©The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.