Sirtuin 1 deficiency mediates chronic kidney disease-induced inflammaging cardiovascular calcification

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Abstract
Chronic kidney disease (CKD) markedly accelerates calcific aortic valve disease (CAVD), yet the underlying mechanisms and therapeutic targets remain poorly defined. Here, we integrate population-scale analyses, single-cell transcriptomics, genetic inference and functional experiments to identify a central role for Sirtuin 1 (SIRT1) in CKD-associated aortic valve calcification. Analysis of UK Biobank data linked CKD to accelerated ageing and increased aortic stenosis risk. Single-cell RNA sequencing of human aortic valves identified SIRT1 downregulation and NLRP3 pathway activation specifically in myofibroblast valve interstitial cells (VICs), coupled with enhanced senescence and osteogenic programmes. Consistently, genetic analyses, including eQTL-based Mendelian randomization, supported an inverse association between SIRT1 expression and CAVD risk. SIRT1 deficiency was associated with enhanced glycolysis, increased NF-κB activation and NLRP3 inflammasome signalling, accompanied by augmented osteogenic differentiation and calcification of VICs. Pharmacological or genetic inhibition of NLRP3 attenuated valve calcification in vivo, establishing the SIRT1-NF-κB-NLRP3 axis as a critical pathway linking CKD to CAVD. Finally, screening of anti-diabetic compounds identified semaglutide as a potent modulator that restores the SIRT1/NLRP3 balance and alleviates calcification in vitro and in vivo. These findings define a metabolic-inflammatory coupling mechanism underlying CKD-induced CAVD and highlight SIRT1 as a therapeutic target. Modulation of the SIRT1-NLRP3 axis, particularly by semaglutide, may represent a promising strategy for preventing valve calcification.
Funding Information
  • National Natural Science Foundation of China (82322007)
  • National Natural Science Foundation of China (82300417)
  • National Natural Science Foundation of China (82170377)
  • National Natural Science Foundation of China (82460073)
  • National Key Research and Development Program of China (2022YFC2503401)

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