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Relationships of Telomere Homeostasis with Oxidative Stress and Cardiac Dysfunction in Human Ischaemic Hearts - PubMed

  • ️Fri Jan 01 2021

Relationships of Telomere Homeostasis with Oxidative Stress and Cardiac Dysfunction in Human Ischaemic Hearts

Estefanía Tarazón et al. Antioxidants (Basel). 2021.

Abstract

Although the roles of telomeres and oxidative stress in ischaemic cardiomyopathy (ICM) are known, mechanisms of telomere homeostasis and their relationship with oxidative stress are incompletely understood. We performed two RNA-seq analyses (mRNA n = 23; ncRNA n = 30) and protein validation on left ventricles of explanted hearts from ICM and control subjects. We observed dysregulation of the shelterin and cohesin complexes, which was related to an increase in the response to cellular oxidative stress. Moreover, we found alterations at mRNA level in the mechanisms of telomeric DNA repair. Specifically, increased RAD51D mRNA levels were correlated with left ventricular diameters. RAD51D protein levels were unaltered, however, and were inversely corelated with the miR-103a-3p upregulation. We also observed the overexpression of lncRNAs (TERRA and GUARDIN) involved in telomere protection in response to stress and alterations in their regulatory molecules. Expression of the TERRA transcription factor ATF7 was correlated with superoxide dismutase 1 expression and left ventricular diameters. The levels of GUARDIN and its transcription factor FOSL2 were correlated with those of catalase. Therefore, we showed specific alterations in the mechanisms of telomeric DNA repair and protection, and these alterations are related to an increase in the response mechanisms to oxidative stress and cardiac dysfunction in ICM.

Keywords: TERRA and GUARDIN; ischaemic cardiomyopathy; oxidative stress response; telomere.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Dot plot graph of mRNA, miRNA and protein expression levels of main molecules associated with telomere homeostasis. (A) Genes of shelterin complex. (B) Genes involved in the maintenance shelterin complex. (C) CTCF and cohesin complex genes. (D) Genes involved in the telomere DNA repair. (E) miRNAs targeting TERF1, POT1, RAD21 and RAD51D. (F) Correlation of RAD51D mRNA levels with left ventricular end-systolic (LVESD) and left ventricular end-diastolic (LVEDD) diameters. (G) TIN2, RAP1, TANK1 and RAD51D protein levels. (H) Correlation of RAD51D protein levels with miR-103a-3p expression levels. (I) Correlation of TIN2 with TANK1 protein levels. The results were obtained by mRNA-sequencing SOLiD 5500XL platform and ncRNA-sequencing Illumina HiSeq 2500 platform. Data are presented as the mean ± SEM. au, arbitrary units. Ischemic cardiomyopathy patients (orange), controls subjects (blue). Left ventricular end-systolic diameter (black), left ventricular end-systolic diameter (grey). * p < 0.05, ** p < 0.01, *** p < 0.0001.

Figure 2
Figure 2

Dot plot graph of lncRNAs expression and mRNA expression levels of altered genes associated with TERRA and GUARDIN regulation. (A) TERRA and GUARDIN expression. (B) Genes involved in TERRA and GUARDIN regulation. (C) Correlation of ATF7 mRNA levels with left ventricular end-systolic (LVESD) and left ventricular end-diastolic (LVEDD) diameters. The results were obtained by mRNA-sequencing SOLiD 5500XL platform and ncRNA-sequencing Illumina HiSeq 2500 platform. Data are presented as the mean ± SEM. au, arbitrary units. Ischemic cardiomyopathy patients (orange), controls subjects (blue). Left ventricular end-systolic diameter (black), left ventricular end-systolic diameter (grey). * p < 0.05, ** p < 0.01.

Figure 3
Figure 3

Dot plot graph of mRNA (n = 23) and miRNA (n = 30) expression levels of altered molecules associated with stress oxidative response. (A) mRNA relative expression levels of altered genes associated with stress oxidative response. (B) miRNAs target SOD1 and CAT. (C) Correlation of ATF7 mRNA levels with SOD1 mRNA levels. (D) Correlation of HMGB2 mRNA levels with SOD1 mRNA levels. (E) Correlation of HMGB2 mRNA levels with SOD3 mRNA levels. (F) Correlation of HMGB2 mRNA levels with CAT mRNA levels. (G) Correlation of GUARDIN mRNA levels with CAT mRNA levels. (H) Correlation of FOSL2 mRNA levels with CAT mRNA levels. The results were obtained by mRNA-sequencing SOLiD 5500XL platform and ncRNA-sequencing Illumina HiSeq 2500 platform. Data are presented as the mean ± SEM. au, arbitrary units. Ischemic cardiomyopathy patients (orange), controls subjects (blue). * p < 0.05, ** p < 0.01.

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