Activation of the cGAS-STING pathway in cardiomyocytes with short telomeres opens new therapeutic avenues to treat heart failure

Accumulating evidence supports a central role of telomere shortening, a hallmark of aging in the pathogenesis of heart failure. In most adult mammalian tissues, including the myocardium, activity of the telomere lengthening enzyme telomerase is negligible, rendering telomere rejuvenation challenging. To identify alternative therapeutic intervention points, we conducted transcriptional profiling of cardiomyocytes from mice with disrupted telomerase activity resulting in increasing telomere shortening with every generation. In generation 5 telomerase deficient mice with aggravated telomere shortening (mTRG5), echocardiography revealed impaired cardiac function and impaired cardiomyocyte mitochondrial function. Analysis of the transcriptome and underlying upstream regulators in mTRG5 vs B6 mice confirmed upregulation of TP53 and repression of PGC-1α as central events in cardiac telomere shortening. Further, we found significant overrepresentation of TNF-α, TGF-β, IFN-γ, IL-1β together with IL-6, angiotensinogen and NFκB revealing a network of neurohumoral dysregulation, inflammation and senescence subsequent to cardiomyocyte telomere shortening. Remarkably, we further discovered a significant downregulation of the regulator TREX1 in mTRG5 compared to B6 mice. Deficiency of this crucial DNA repair enzyme leads to the accumulation of cytoplasmic DNA, a potent inducer of cGAS-STING signaling. Following this path, we aligned our mTRG5 vs B6 data with the profile of TREX1-/- vs B6 mice (NCBI GEO), which exhibit inflammatory myocarditis. As anticipated, TREX1-/- vs B6 mice exhibit a pronounced increase in regulators of the cGAS-STING pathway, including CGAS (z-score 10.9/p-value 10E-76), STING1 (8.1/10E-55), IFNAR (11.6/10E-73), and IFNG (12.3/10E-79). Notably, we observed a similarly pronounced cGAS-STING activation in mTRG5 vs B6 mice: CGAS (8.6/10E-40), STING1 (5.1/10E-43), IFNAR (9.1/10E-35), and IFNG (7.9/10E-44). Furthermore, the knockout of the crucial adaptor protein TMEM173 in TREX1-/- mice effectively reversed the activation of all regulators, confirming the involvement of cGAS-STING but also suggesting novel therapeutic approaches. Transcriptional profiling of telomere-shortened cardiomyocytes unveiled a network integrating neurohumoral activation, inflammation, and senescence, which we could confirm in numerous HF datasets across species and etiologies by analysis matching. Specifically, the revelation of elevated cGAS-STING signaling in telomere shortened cardiomyocytes and in heart failure datasets identified direct potential targets that, upon further validation in subsequent studies, could be reasonably approached to extend heart failure therapy.