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. 2023 Nov 9;24(22):16127.
doi: 10.3390/ijms242216127.

Analysis of ANRIL Isoforms and Key Genes in Patients with Severe Coronary Artery Disease

Francisco Rodríguez-Esparragón  1   2   3   4 , Laura B Torres-Mata  1   2   5 , Sara E Cazorla-Rivero  1   2   6 , Jaime A Serna Gómez  1   2   7 , Jesús M González Martín  1   2   8 , Ángeles Cánovas-Molina  1   2   9 , José A Medina-Suárez  1   2   5 , Ayose N González-Hernández  1   2   10 , Lidia Estupiñán-Quintana  1   2 , María C Bartolomé-Durán  1   2 , José C Rodríguez-Pérez  11 , Bernardino Clavo Varas  1   2   3   4   9   12   13   14
Affiliations

Analysis of ANRIL Isoforms and Key Genes in Patients with Severe Coronary Artery Disease

Francisco Rodríguez-Esparragón et al. Int J Mol Sci. .

Abstract

ANRIL (Antisense Noncoding RNA in the INK4 Locus), also named CDKN2B-AS1, is a long non-coding RNA with outstanding functions that regulates genes involved in atherosclerosis development. ANRIL genotypes and the expression of linear and circular isoforms have been associated with coronary artery disease (CAD). The CDKN2A and the CDKN2B genes at the CDKN2A/B locus encode the Cyclin-Dependent Kinase inhibitor protein (CDKI) p16INK4a and the p53 regulatory protein p14ARF, which are involved in cell cycle regulation, aging, senescence, and apoptosis. Abnormal ANRIL expression regulates vascular endothelial growth factor (VEGF) gene expression, and upregulated Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis by activating the NF-κB signaling pathway. Here, we explored associations between determinations of the linear, circular, and linear-to-circular ANRIL gene expression ratio, CDKN2A, VEGF and its receptor kinase insert domain-containing receptor (KDR) and cardiovascular risk factors and all-cause mortality in high-risk coronary patients before they undergo coronary artery bypass grafting surgery (CABG). We found that the expression of ANRIL isoforms may help in the prediction of CAD outcomes. Linear isoforms were correlated with a worse cardiovascular risk profile while the expression of circular isoforms of ANRIL correlated with a decrease in oxidative stress. However, the determination of the linear versus circular ratio of ANRIL did not report additional information to that determined by the evaluation of individual isoforms. Although the expressions of the VEFG and KDR genes correlated with a decrease in oxidative stress, in binary logistic regression analysis it was observed that only the expression of linear isoforms of ANRIL and VEGF significantly contributed to the prediction of the number of surgical revascularizations.

Keywords: CDKN2A; CDKN2B-AS1 (ANRIL); KDR; VEGF; cardiovascular risk; coronary artery disease; gene expression; outcome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Linear ANRIL expression and (b) linear-to-circular ANRIL expression ratio correlated with BMI in CAD patients. Each position of a point on the graph is determined by the values of both variables for that observation. The points with darker colors occur when observations overlap.
Figure 2
Figure 2
Boxplots of the (a) logarithm of the ANRIL linear expression, (b) logarithm of linear-to-circular ANRIL expression ratio, and (c) logarithm of the CDKN2A gene expression according to the number of affected vessels. * p < 0.005.
Figure 3
Figure 3
Boxplots of the (a) logarithm of the ANRIL linear expression, (b) logarithm of linear-to-circular ANRIL expression ratio, and (c) logarithm of the CDKN2A gene expression according to the number of revascularization procedures. * p < 0.05.
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