Background: Aortic valve stenosis (AVS), which is the most common valvular heart disease, causes a progressive narrowing of the aortic valve as a consequence of thickening and calcification of the aortic valve leaflets. The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in cardiovascular prevention have recently been demonstrated in a large randomized, controlled trial. In addition, n-3 PUFAs serve as the substrate for the synthesis of specialized proresolving mediators, which are known by their potent beneficial anti-inflammatory, proresolving, and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and specialized proresolving mediators on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA–derived specialized proresolving mediators in relation to the development of AVS. Methods: Lipidomic and transcriptomic analyses were performed in human tricuspid aortic valves. Apoe −/− mice and wire injury in C57BL/6J mice were used as models for mechanistic studies. Results: We found that n-3 PUFA incorporation into human stenotic aortic valves was higher in noncalcified regions compared with calcified regions. Liquid chromatography tandem mass spectrometry–based lipid mediator lipidomics identified that the n-3 PUFA–derived specialized proresolving mediator resolvin E1 was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe −/− mice expressing the Caenorhabditis elegans Fat-1 transgene (Fat-1 tg ×Apoe −/− ), which enables the endogenous synthesis of n-3 PUFA and increased valvular n-3 PUFA content, exhibited reduced valve calcification, lower aortic valve leaflet area, increased M2 macrophage polarization, and improved echocardiographic parameters. Finally, abrogation of the resolvin E1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1 tg were abolished in the absence of ChemR23. Conclusions: n-3 PUFA-derived resolvin E1 and its receptor ChemR23 emerge as a key axis in the inhibition of AVS progression and may represent a novel potential therapeutic opportunity to be evaluated in patients with AVS.

Valvular and arterial function are tightly intertwined, both in terms of structural changes and hemodynamics. While proximal valvulo-vascular coupling contributes to the cardiovascular consequences of aortic stenosis, less is known on how peripheral arterial stiffness relates to aortic valve disease. Previous studies have shown conflicting results regarding the impact of aortic valve replacement on arterial stiffness. The aim of the present study was therefore to determine predictors of arterial stiffness in patients with and without aortic valve disease undergoing cardiac surgery. Cardio ankle vascular index (CAVI) and carotid femoral pulse wave velocity (cfPWV) were measured to determine arterial stiffness the day before and 3 days after surgery for either ascending aortic or aortic valve disease. Stratification on indication for surgery revealed that CAVI was significantly lower in patients with aortic valve stenosis (n = 45) and aortic valve regurgitation (n=30) compared with those with isolated ascending aortic dilatation (n = 13). After surgery, a significant increased CAVI was observed in aortic stenosis (median 1.34, IQR 0.74–2.26, p < 0.001) and regurgitation (median 1.04, IQR 0.01–1.49, p = 0.003) patients while cfPWV was not significantly changed. Age, diabetes, low body mass index, low pre-operative CAVI, as well as changes in ejection time were independently associated with increased CAVI after surgery. The results of the present study suggest aortic valve disease as cause of underestimation of arterial stiffness when including peripheral segments. We report cardiovascular risk factors and pinpoint the hemodynamic aspect ejection time to be associated with increased CAVI after aortic valve surgery.

Background: Palmdelphin (PALMD) belongs to the family of Paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms (SNPs) in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis (CAVS) and predict severity of the disease. Methods: Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, co-immunoprecipitation and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in siRNA-treated EC cultures, in knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the SNP rs7543130, informed about gene regulatory changes. Results: ECs express the cytosolic PALMD-KKVI splice variant, which associated with RAN GTPase activating protein1 (RANGAP1). RANGAP1 regulates the activity of the GTPase RAN and thereby, nucleocytoplasmic shuttling via Exportin1 (XPO1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently, in gene regulation due to the impact on localization of transcriptional regulators. Changes in EC responsiveness upon loss of PALMD expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in PALMD -deficient ECs, Palmd −/− mouse aorta and human aortic valve samples derived from CAVS patients. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in PALMD -silenced ECs. Conclusions: We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced PALMD expression provide a mechanistic underpinning for PALMD's contribution to CAVS pathology.