Fuelling aortic stenosis: the integral role of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3-mediated glycolysis in Lp(a)-induced valve inflammation.

Abstract

Aims: Calcific aortic valve disease is the most common valvular heart disease characterized by an inflammatory response in the leaflets followed by fibro-calcific remodelling of valvular interstitial cells (VICs). Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for CAVD, however the role of metabolism in driving Lp(a)-induced inflammation remains largely elusive. Therefore, we aim to investigate the role of Lp(a) in driving inflammatory and metabolic changes in VICs and examine how alterations in cellular metabolism can alter their inflammatory phenotype.

Methods and results: Inflammatory activity in the aortic valve of patients with mild to severe aortic stenosis with elevated Lp(a) levels (>50 mg/dL) is increased, as reflected by increased ¹⁸F-FDG uptake in the aortic valve, compared with those with low Lp(a) levels (<50 mg/dL) with a maximal TBR of 1.60 ± 0.20 vs. 1.43 ± 0.16 (P < 0.002). RNA-seq analysis of VICs stimulated with a physiological relevant concentration Lp(a) revealed that Lp(a)-induced inflammation in vitro initially occurs in an NF-κB-dependent manner, but switches to glycolysis driven inflammation after long-term exposure. Glucose uptake, lactate secretion and maximal glycolytic capacity were increased by Lp(a) via the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), while inhibition of PFKFB3 results in a 50% reduction of Lp(a)-induced cytokine gene expression and secretion.

Conclusion: Lipoprotein(a)-induced PFKFB3-mediated glycolysis in VICs sustains NF-κB-dependent inflammatory response. These insights into the inflammation-metabolic axis may offer a more refined approach to decrease valvular inflammation.