Differential endothelial senescence elicited by AQP1 regulation of epigenetic/metabolic responses

Abstract Introduction Accumulation of senescent endothelial cells with age is an important driver vascular aging and related cardiovascular disease. However, little known about the mechanisms signaling pathways that underpin cell senescence. Aquaporin-1 (AQP1) has been implicated in sensing hydrogen peroxide (H2O2), which differentially modulates signal transduction. Nonetheless, role AQP1 regulation metabolism function young old remains elusive. Purpose We sought to investigate whether 1) regulates senescence angiogenesis through epigenetic/metabolic response, senescence-associated secretory phenotype (SASP), 2) knockdown/inhibition rejuvenates restores angiogenesis. Methods assessed impaired mitochondrial metabolic disorder, epigenetic alteration, SASP human aortic aortas from wild-type C57BL/6 mice. For these, we conducted knockdown (with siRNA) or blockade Bacopaside-II, 10 μM) inhibit H2O2 transport. Results Here show upregulation (SEC, p.15) aorta mice (>24 months) (p<0.01 p<0.0001, respectively), facilitating outside-in Interestingly, reverses both replicative (increased SA-β-galactosidase positive cells) stress-induced cell-cycle arrest markers p16, p19, p21; IL1α, IL1β, IL6) SEC, whereas it triggers processes proliferating (PEC, p.5) (for each, p<0.05, n=6). Unlike PEC (3-month-old), SEC aortas. The interventions increased OXPHOS (represented by enhanced oxygen consumption rate (OCR)) accompanied marked increase CaMKKβ-regulated AMPKT172 phosphorylation n=6) histone deacetylase-4 (HDAC4) at Ser632 (p<0.05) further 3 (H3) acetylation (p<0.01). HDAC4 leads significant Mef2A-mediated eNOS Ser1177 (p<0.05). By contrast, induced a senescent-like state decrease OCR CaMKKβ-AMPK HDAC4-Mef2A activity. Conclusion Our studies identify as essential regulator EC proliferation via response modulation. Moreover, genetic pharmacological inhibition angiogenesis, representing potential therapeutic target for rejuvenation. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Swiss Science Foundation (SNSF)SwissLife Jubiläumsstiftung