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

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.

Implication of Sphingolipid Metabolism Gene Dysregulation and Cardiac Sphingosine-1-Phosphate Accumulation in Heart Failure

“…RNA extraction, determination of purity and integrity of RNA samples, mRNA-seq, and ncRNA-seq analysis were performed as previously described by Tarazón et al [ 14 ] and are extensively described in the Supplementary Materials .…”

Altered MicroRNA Maturation in Ischemic Hearts: Implication of Hypoxia on XPO5 and DICER1 Dysregulation and RedoximiR State

“…It constitutes a significant economic and public health burden with high morbidity and mortality rates worldwide [1], mainly due to ischemic heart diseases, and is a leading global cause of death [2]. The pathological process of the heart is associated with an altered expression profile of molecules that are important for cardiac function [3][4][5][6]; however, the molecular mechanisms of gene regulation remain incompletely understood. Most human protein-coding genes are likely under microRNA control through microRNA-binding sites located in their untranslated and amino acid coding regions [7,8] and, therefore, microRNA are probably involved in nearly all developmental and pathological processes.…”

Oxidative Stress in Cardiovascular Disease and Comorbidities

“…In the context of myocardial damage in ischaemic heart disease, Tarazón et al [ 7 ] explore telomere homeostasis and its relationship with oxidative stress as a novel potential mechanism and biomarker. Through RNA-seq studies of left ventricular samples of explanted hearts from ischaemic cardiomyopathy patients and control subjects, the authors observed a dysregulation of the shelterin and cohesin complexes, associated with an increase in the response to cellular oxidative stress.…”