Integrative transcriptomic profiling links telomere dysfunction to cGAS–STING activation in heart failure signatures in mice and humans

Abstract Aims Cardiomyocyte telomere shortening is evident during heart failure pathogenesis. Conversely, mice with engineered telomerase deficiency develop myocardial dysfunction accompanied by p53 activation and mitochondrial repression. Yet, critical aspects remain to be established: whether cardiac dysfunction in mice lacking telomerase components arises from myocardial-intrinsic effects or systemic consequences of telomere shortening, which broader transcriptional programs follow cardiomyocyte telomere shortening, and what implications these carry for clinical heart failure. Methods and Results As a prerequisite, we generated telomerase-deficient mice across successive generations and confirmed increasing cardiac dysfunction by comprehensive cardiovascular phenotyping and assessment of mitochondrial function in isolated cardiomyocytes. Transcriptional and regulator analysis confirmed the telomere–p53–mitochondria axis but extended beyond it, revealing additional involvement of neurohumoral activation, senescence, and inflammation, notably type I interferon signaling. To contextualize these findings, we compared this profile with hypertensive heart failure induced by neurohumoral dysregulation (angiotensin II infusion, nephrectomy, salt overload; ANS model) and established a transcriptional hierarchy. In mTRG5 mice, regulators of telomere dysfunction and p53 activation ranked highest by significance and centrality, supporting telomere shortening as the primary upstream driver. In contrast, ANS mice showed higher-ranking neurohumoral regulators, indicating these govern secondary pathways. To pursue the strong type 1 interferon profile, we utilized myocardial profiles of mice with a lack of three-prime exonuclease 1 (TREX1), an established activator of the cGAS-STING pathway. Matching the profiles, we could confirm pronounced activity of cGAS-STING in mTRG5- and to a lesser degree in ANS mice and thus provide first evidence for cGAS-STING-activation in telomere shortening and heart failure. Conclusion Finally, comparing the mTRG5 profile to curated datasets of human and murine dilated- and ischemic cardiomyopathy revealed a robust statistical overlap, proportional to the heart failure severity in mice and man, fostering the clinical relevance.