Liraglutide Attenuates Endothelial Dysfunction by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the LARP7/SIRT1 Pathway

Zhong, Weili; Yang, Ying; Wang, Yanru

doi:10.2478/aite-2026-0006

Abstract

Vascular endothelial cells (ECs) are pivotal in maintaining vascular homeostasis. Liraglutide (LIR) can prevent and reverse hyperglycemia-induced cell dysfunction. However, the mechanism by which it improves hyperglycemia-induced EC senescence remains unclear. This study investigates whether the La Ribonucleoprotein 7/Sirutin 1 (LARP7/SIRT1) signaling axis is essential for LIR efficacy in mitigating EC senescence and dysfunction. We treated senescent human umbilical vein ECs induced by high glucose levels with LIR and evaluated cell viability cell counting kit-8 (CCK-8 assay), senescence (SA-β-gal staining), and SASP alterations (qPCR). We also investigated the expression of senescence-related proteins and changes in the LARP7/SIRT1 signaling pathway using Western blot analysis. Additionally, reactive oxygen species levels were measured with 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA), and changes in oxidative stress-related factors were assessed using specific assay kits. The effect of LIR on endothelial dysfunction was examined by cellular tube-forming assay and transwell assay after LARP7 knockdown/overexpression. LIR markedly improved cell vitality and the senescence phenotype while reducing oxidative stress. The LARP7/SIRT1 pathway emerged as crucial for its effectiveness. Following LARP7 knockdown, the therapeutic efficacy of LIR was notably attenuated. The overexpression of LARP7 enhanced the therapeutic efficacy of LIR. The tube formation and transwell assays further supported the hypothesis that LIR's beneficial impact on endothelial dysfunction depends on the LARP7/SIRT1 signaling axis. Our study reveals a novel aspect of LIR as an antidiabetic agent in delaying vascular aging driven by high glucose through targeting the LARP7/SIRT1 pathway. This discovery enhances the therapeutic value of LIR and proposes a new strategy for addressing vascular aging in treatments for elderly patients with diabetes.

References

Abdel Ghafar MT, Gharib F, Abdel-Salam S et al. (2020) Role of serum metadherin mRNA expression in the diagnosis and prediction of survival in patients with colorectal cancer. Mol Biol Rep 47:2509–2519. https://doi.org/10.1007/s11033-020-05334-5
Search in Google Scholar Back to article
Abdel-Reheim MA, Zaafar D, El-Shoura EAM et al. (2024) Unlocking the miRNA-34a-5p/TGF-β and HMGB1/PI3K/Akt/mTOR crosstalk participate in the enhanced cardiac protection of liraglutide against isoproterenol-induced acute myocardial injury rat model. Int Immunopharmacol 127:111369. https://doi.org/10.1016/j.intimp.2023.111369
Search in Google Scholar Back to article
Bako KR, Mohammadnezhad M, Sika-Paotonu D et al. (2024) Diabetes cam: an objective methodology to study diabetes self-management. Am J Prev Med 66:909–913. https://doi.org/10.1016/j.amepre.2023.12.016
Search in Google Scholar Back to article
Chin T, Lee XE, Ng PY et al. (2023) The role of cellular senescence in skin aging and age-related skin pathologies. Front Physiol 14:1297637. https://doi.org/10.3389/fphys.2023.1297637
Search in Google Scholar Back to article
Daniali M, Nikfar S, Abdollahi M (2024) Advancements in pharmacotherapy options for treating diabetes in children and adolescents. Expert Rev Endocrinol Metab 19:37–47. https://doi.org/10.1080/17446651.2023.2290491
Search in Google Scholar Back to article
El-Osta A (2023) Transcriptional control of endothelial senescence and vascular repair. Circ Res 133:858–860. https://doi.org/10.1161/CIRCRESAHA.123.323716
Search in Google Scholar Back to article
Fathy MA, Anbaig A, Aljafil R et al. (2023) Effect of liraglutide on osteoporosis in a rat model of type 2 diabetes mellitus: a histological, immunohistochemical, and biochemical study. Microsc Microanal 29:2053–2067. https://doi.org/10.1093/micmic/ozad102
Search in Google Scholar Back to article
Guo T, Yan W, Cui X et al. (2023) Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis. Mol Med 29:132. https://doi.org/10.1186/s10020-023-00721-7
Search in Google Scholar Back to article
He W, Wang H, Zhao C et al. (2020) Role of liraglutide in brain repair promotion through Sirt1-mediated mitochondrial improvement in stroke. J Cell Physiol 235:2986–3001. https://doi.org/10.1002/jcp.29204
Search in Google Scholar Back to article
Inoue T, Inoguchi T, Sonoda N et al. (2015) GLP-1 analog liraglutide protects against cardiac steatosis, oxidative stress and apoptosis in streptozotocin-induced diabetic rats. Atherosclerosis 240:250–259. https://doi.org/10.1016/j.atherosclerosis.2015.03.026
Search in Google Scholar Back to article
Kalinin A, Zubkova E, Menshikov M (2023) Integrated stress response (ISR) pathway: unraveling its role in cellular senescence. Int J Mol Sci 24:17423. https://doi.org/10.3390/ijms242417423
Search in Google Scholar Back to article
Lee YS, Park YH, Hwang G et al. (2024) Cpne7 deficiency induces cellular senescence and premature aging of dental pulp. Aging Cell 23:e14061. https://doi.org/10.1111/acel.14061
Search in Google Scholar Back to article
Liang X, Wu S, Geng Z et al. (2021) LARP7 suppresses endothelial-to-mesenchymal transition by coupling with TRIM28. Circ Res 129:843–856. https://doi.org/10.1161/CIRCRESAHA.121.319590
Search in Google Scholar Back to article
Liao J, Fu L, Tai S et al. (2024) Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: a 4D label-free quantitative proteomics and network pharmacology study. J Ethnopharmacol 321:117550. https://doi.org/10.1016/j.jep.2023.117550
Search in Google Scholar Back to article
Liu H, Ghosh S, Vaidya T et al. (2023) Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy. JCI Insight 8:e168945. https://doi.org/10.1172/jci.insight.168945
Search in Google Scholar Back to article
Li Y, Wu Y, Ning Z et al. (2023) Echinacoside ameliorates 5-fluorouracil-induced endothelial injury and senescence through SIRT1 activation. Int Immunopharmacol 120:110279. https://doi.org/10.1016/j.intimp.2023.110279
Search in Google Scholar Back to article
Lord SM, Bahnson HT, Greenbaum CJ et al. (2023) Testing a new platform to screen disease-modifying therapy in type 1 diabetes. PLoS One 18:e0293268. https://doi.org/10.1371/journal.pone.0293268
Search in Google Scholar Back to article
Mennie AK, Moser BA, Nakamura TM (2018) LARP7-like protein Pof8 regulates telomerase assembly and poly(A)+TERRA expression in fission yeast. Nat Commun 29:586. https://doi.org/10.1038/s41467-018-02874-0
Search in Google Scholar Back to article
Miao L, Zhou C, Zhang H et al. (2023) Portulaca oleracea L. (Purslane) extract protects endothelial function by reducing endoplasmic reticulum stress and oxidative stress through AMPK activation in diabetic obese mice. Antioxidants 12:2132. https://doi.org/10.3390/antiox12122132
Search in Google Scholar Back to article
Molnár AÁ, Pásztor DT, Tarcza Z et al. (2023) Cells in atherosclerosis: focus on cellular senescence from basic science to clinical practice. Int J Mol Sci 24:17129. https://doi.org/10.3390/ijms242417129
Search in Google Scholar Back to article
O'Donnell C, Crilly S, O'Mahony A et al. (2024) Continuous positive airway pressure but not GLP1-mediated weight loss improves early cardiovascular disease in obstructive sleep apnea: a randomized proof-of-concept study. Ann Am Thorac Soc 21:464–473. https://doi.org/10.1513/AnnalsATS.202309-821OC
Search in Google Scholar Back to article
Páez-Moscoso DJ, Ho DV, Pan L et al. (2022) A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis. Nat Commun 13:1067. https://doi.org/10.1038/s41467-022-28545-9
Search in Google Scholar Back to article
Palanca A, Ampudia-Blasco FJ, Calderón JM et al. (2024) Comparison of GLP-1 receptor agonists and other glucose-lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and obesity: a Spanish real-world population-based study. Diabetes Res Clin Pract 207:111071. https://doi.org/10.1016/j.diabres.2023.111071
Search in Google Scholar Back to article
Paneni F, Diaz Cañestro C, Libby P et al. (2017) The aging cardiovascular system: understanding it at the cellular and clinical levels. J Am Coll Cardiol 69:1952–1967. https://doi.org/10.1016/j.jacc.2017.01.064
Search in Google Scholar Back to article
Pulipaka S, Singuru G, Sahoo S et al. (2024) Therapeutic efficacies of mitochondria-targeted esculetin and metformin in the improvement of age-associated atherosclerosis via regulating AMPK activation. Geroscience 46:2391–2408. https://doi.org/10.1007/s11357-023-01015-w
Search in Google Scholar Back to article
Ren X, Cui Z, Zhang Q et al. (2024) JunB condensation attenuates vascular endothelial damage under hyperglycemic condition. J Mol Cell Biol 15:mjad072. https://doi.org/10.1093/jmcb/mjad072
Search in Google Scholar Back to article
Santinha D, Vilaça A, Estronca L et al. (2024) Remodelling of the cardiac extracellular matrix proteome during chronological and pathological ageing. Mol Cell Proteomics 23:100706. https://doi.org/10.1016/j.mcpro.2023.100706
Search in Google Scholar Back to article
Savić R, Yang J, Koplev S et al. (2023) Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence. Cell Rep 42:113371. https://doi.org/10.1016/j.celrep.2023.113371
Search in Google Scholar Back to article
Sourris KC, Ding Y, Maxwell SS et al. (2023) Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation. Kidney Int 105:132–149. https://doi.org/10.1016/j.kint.2023.09.029
Search in Google Scholar Back to article
Thijssen DHJ, Bruno RM, van Mil ACCM et al. (2019) Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. Eur Heart J 2019:2534–2547. https://doi.org/10.1093/eurheartj/ehz350
Search in Google Scholar Back to article
Wang Y, Sui Y, Niu Y et al. (2023) PBX1-SIRT1 positive feedback loop attenuates ROS-mediated HF-MSC senescence and apoptosis. Stem Cell Rev Rep 19:443–454. https://doi.org/10.1007/s12015-022-10425-w
Search in Google Scholar Back to article
Wang L, Zhang X, Huang X et al. (2024) Homoplantaginin alleviates high glucose-induced vascular endothelial senescence by inhibiting mtDNA-cGAS-STING pathway via blunting DRP1-mitochondrial fission-VDAC1 axis. FASEB J 38:e70127. https://doi.org/10.1096/fj.202401299RR
Search in Google Scholar Back to article
Yang Y, Liu S, Egloff S et al. (2022) Structural basis of RNA conformational switching in the transcriptional regulator 7SK RNP. Mol Cell 82:1724–1736.e1727. https://doi.org/10.1016/j.molcel.2022.03.001
Search in Google Scholar Back to article
Yan P, Li Z, Xiong J et al. (2021) LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity. Cell Rep 37:110038. https://doi.org/10.1016/j.celrep.2021.110038
Search in Google Scholar Back to article
Yu H, Zhang F, Yan P et al. (2021) LARP7 protects against heart failure by enhancing mitochondrial biogenesis. Circulation 143:2007–2022. https://doi.org/10.1161/CIRCULATIONAHA.120.050812
Search in Google Scholar Back to article
Zhang C, Gu L, Xie H et al. (2024) Glucose transport, transporters and metabolism in diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 1870:166995. https://doi.org/10.1016/j.bbadis.2023.166995
Search in Google Scholar Back to article
Zhu SL, Wang ML, He YT et al. (2022) Capsaicin ameliorates intermittent high glucose-mediated endothelial senescence via the TRPV1/SIRT1 pathway. Phytomedicine 100:154081. https://doi.org/10.1016/j.phymed.2022.154081
Search in Google Scholar Back to article

Liraglutide Attenuates Endothelial Dysfunction by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the LARP7/SIRT1 Pathway

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