Telomere shortening in hypertensive heart disease depends on NOX2-mediated loss of PRDX1 and oxidative DNA damage

Abstract Background Heart failure (HF) coincides with cardiomyocyte telomere shortening. Arterial hypertension is the most prominent risk factor for HF. Both HF and arterial are associated dysregulation of neurohormonal axis increased ROS. However, how activation linked to shortening in pathogenesis incompletely understood. Further, recent findings suggest that peroxiredoxin 1 (PRDX1) can act as a specific antioxidant. Methods To induce hypertensive HF, male C57BL/6J mice were subjected AngII-infusion, uninephrectomy high-salt (AngII++) 5 weeks. Cardiac function was assessed by ultrasound. Mouse adult cardiomocytes (CMs) isolated from lacking NADPH-oxidase (NOX) 2/gp91phox well rat ventricular CM-derived cells (H9C2) stimulated AngII. Telomere length quantified Q-FISH after staining C-rich probe (TelC). DNA/RNA-damage evaluated Oxo-8-Gua (8-oxo-7,8-dihydroguanine) Oxo-8-G (8-oxo-7,8-dihydroguanosine). Superoxide (O2-) 2-hydroxyethidium (2-HE) using HPLC analysis. Colocalization TelC automated image (Sub)cellular tissue expression gp91phox/Nox2 PRDX1 ICC/IHC. All quantification conducted semiautomatically. Results In CM correlated significantly both left (LV) dilatation impairment LV systolic function, paralleled significant loss myocardial DNA/RNA-damage. Similarly, CMs AngII exhibited shortening, DNA/RNA-damage, together superoxide production generating enzyme gp91phox/NOX2. Correspondingly, deficiency gp91phox/NOX2 prevented AngII-induced PRDX1-depletion. A similar effect could be observed upon stimulation histone deacetylase (HDAC) 6-inhibitor tubastatin, which prevents deacetylation PRDX1. Conclusion We provide first evidence heart failure, ROS originating NOX2-activity leads depletion telomere-targeted antioxidant repair-protein PRDX1, results damage telomeric DNA. NOX2 harnessing intrinsic defense stabilizing via HDAC6-inhibition further potential therapeutic targets address failure. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): German Federal Ministry Education Research