Telomere 3'-overhang attrition and persistent telomeric DNA damage response in failing human hearts

Abstract

Background: Telomere homeostasis is critical for normal cellular and organ function, and its dysregulation is implicated in aging and chronic diseases. Although telomere length (TL) is critical for normal telomere function, its functional status can also be altered by many other factors. The organization and protective status of telomere in failing human heart (FHH) remains incompletely understood. Methods: Using left ventricular tissues from patients with idiopathic dilated cardiomyopathy (IDC), ischemic heart disease (IHD), and non-failing heart (NFH), we performed a comprehensive analysis that included measurements of overall TL and 3\' overhang length in left ventricles and cardiomyocytes (CM), assessment of telomere-binding protein associations, and transcriptomic profiling through RNA sequencing. Results: Although TL varied among individuals, reduced median TL was observed only in IDC, while both IDC and IHD showed an increased frequency of very short telomeres, falling below the 5th percentile, in CMs. Strikingly, significant telomere 3\'-overhang attrition was detected in both disease groups and strongly correlated with elevated H2AX phosphorylated on serine 139 ({gamma}H2AX) in heart tissues, indicating DNA damage. This was accompanied by persistent activation of ataxia telangiectasia mutated (ATM) protein-mediated DNA damage responses and the formation of telomere dysfunction-induced foci (TIFs) in CMs from FHH. Concomitantly, the association of telomeres with the single-stranded telomere-binding protein, Protection of Telomeres 1 (POT1), and the double-stranded telomere-interacting protein, telomere repeat-binding factor 2 (TERF2), was markedly reduced, accompanied by an increase in association of {gamma}H2AX and ssDNA binding protein, RPA with telomeres in IDC and IHD relative to NFH, signifying telomere de-protection. Conclusions: CM telomere dysfunction, characterized by 3\' overhang attrition and de-protection, is a common feature in FHH, leading to persistent DNA damage response in telomeres. Better understanding of telomere biology throughout the progression of different heart diseases to heart failure will provide more effective prevention and treatment strategies.