Abstract Number: PB0131
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Animal Models in Thrombosis and Hemostasis
Background: Extreme telomere shortening has been shown to impair cardiac function. Also first evidence suggests that heart failure (HF) might in turn result in telomere attrition. However, the responsible pathomechanism in the affected tissues remains completely obscure.
Aims: We investigated what degree of telomere shortening is elicited by myocardial injury via excess neurohormonal activation (NHA), the key factor driving HF, and what sequelae result. NHA is known to induce elevated levels of reactive oxygen species (ROS), which due to the susceptible telomeric ultrastructure seems a plausible candidate causing the shortening process.
Methods: By subjecting C57BL/6J (B6) mice to infusion of angiotensin II (AngII), unilateral nephrectomy and high-salt diet we induced excess NHA. Cardiac function was determined by ultrasound. H9c2-cardiomyocytes (CMs) were incubated with AngII and H2O2 to assess the effect of NHA and ROS directly on telomere length (TL) in vitro. Oxidative stress levels were detected by the MitoSOX assay. TL was measured by quantitative fluorescence in situ hybridization (Q-FISH) in H9c2, isolated mouse CMs and peripheral blood mononuclear cells (PBMCs).
Results: NHA resulted in significant hypertrophy and impaired systolic function after 5 weeks paralleled by significant telomere shortening in CMs and PBMCs compared to controls (length CMs: B6 1.0, NHA 0.82; PBMCs: B6 1.0, NHA 0.8). Stimulation of H9c2 cells with AngII for 4h resulted in 20% shortened telomeres and MitoSOX measurements revealed an increase of oxidative stress of 11% compared to untreated cells.
Conclusions: Excess NHA-induced heart failure is associated with increased ROS production and significant telomere shortening. Further, the degree of telomere shortening appears to correlate with the pathological status of the affected myocardium. The PBMCs seem to mimic these myocardial patterns. These data strongly suggest a causative role of telomere shortening-induced signalling pathways in the pathogenesis of HF, even after moderate telomere shortening, and further points towards ROS as the culprit.
To cite this abstract in AMA style:
Dörschmann H, Brandt M, Garlapati V, Münzel T, Wenzel P. Heart Failure, Induced by Excess Neurohormonal Activation, Results in Significant but Non-Critical Telomere Shortening in Cardiomyocytes and Peripheral Blood Mononuclear Cells [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/heart-failure-induced-by-excess-neurohormonal-activation-results-in-significant-but-non-critical-telomere-shortening-in-cardiomyocytes-and-peripheral-blood-mononuclear-cells/. Accessed May 6, 2021.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/heart-failure-induced-by-excess-neurohormonal-activation-results-in-significant-but-non-critical-telomere-shortening-in-cardiomyocytes-and-peripheral-blood-mononuclear-cells/