Semaglutide restores SIRT1/NLRP3 balance, alleviating chronic kidney disease-induced aortic valve calcification

Calcific aortic valve disease (CAVD) is a prevalent and challenging condition, especially in patients with chronic kidney disease (CKD), where it progresses rapidly. Currently, there are no effective pharmacological treatments for CAVD, leaving surgical valve replacement as the only option. Understanding the underlying mechanisms linking CKD to accelerated CAVD is crucial for developing therapeutic strategies. This research investigates the role of Sirtuin 1 (SIRT1), a key regulator of cellular metabolism and inflammation, as a potential mediator in this complex pathology.

Researchers integrated population-scale analyses from the UK Biobank, single-cell RNA sequencing (scRNA-seq) of human aortic valves, genetic inference (including eQTL-based Mendelian randomization), and functional experiments. They investigated the role of SIRT1 in myofibroblast valve interstitial cells (VICs) and its link to CKD-associated CAVD. Functional experiments involved in vitro studies on VICs and in vivo models of valve calcification. A screening of anti-diabetic compounds was performed to identify modulators of the SIRT1/NLRP3 balance, ultimately identifying semaglutide as a potent candidate.

Analysis of UK Biobank data linked CKD to accelerated aging and increased aortic stenosis risk. Single-cell RNA-seq of human aortic valves revealed significant SIRT1 downregulation and NLRP3 pathway activation specifically in myofibroblast VICs, correlating with enhanced senescence and osteogenic programs. Genetic analyses further supported an inverse association between SIRT1 expression and CAVD risk. SIRT1 deficiency was associated with enhanced glycolysis, increased NF-κB activation, and NLRP3 inflammasome signaling, leading to augmented osteogenic differentiation and calcification of VICs. Pharmacological or genetic inhibition of NLRP3 attenuated valve calcification in vivo.

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.