| 1. |
- Artiach, Gonzalo, et al.
(författare)
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Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease through the Resolvin E1 and ChemR23 Axis.
- 2020
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 142, s. 776-789
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Tidskriftsartikel (refereegranskat)abstract
- 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 PUFA) in cardiovascular prevention have been recently demonstrated in a large randomized controlled trial. In addition, n-3 PUFA serve as the substrate for the synthesis of specialized pro-resolving mediators (SPMs), which are known by their potent beneficial anti-inflammatory, pro-resolving and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and SPMs on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA-derived SPMs 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 non-calcified regions compared with calcified regions. LC-MS-MS based lipid mediator lipidomics identified that the n-3 PUFA-derived SPM resolvin E1 (RvE1) was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe-/- mice expressing the Caenorhabditis elegans Fat-1 transgene (Fat-1tgxApoe-/-), which enables the endogenous synthesis of n-3 PUFA, 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 RvE1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1tg were abolished in the absence of ChemR23. Conclusions: n-3 PUFA-derived RvE1 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.
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| 2. |
- Bäck, Magnus, et al.
(författare)
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Fatty acid desaturase genetic variations and dietary omega-3 fatty acid intake associate with arterial stiffness
- 2022
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Ingår i: European Heart Journal Open. - : Oxford University Press. - 2752-4191. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Long-chain polyunsaturated fatty acids (PUFAs) generate diverse bioactive lipid mediators, which tightly regulate vascular inflammation. The effects of omega-3 PUFA supplementation in cardiovascular prevention however remain controversial. In addition to direct dietary intake, fatty acid desaturases (FADS) determine PUFA levels. Increased arterial stiffness represents an independent predictor of mortality and cardiovascular events. The aim of the present study was to determine the association of PUFA intake, FADS1 genotype, and FADS expression with arterial stiffness.METHODS AND RESULTS: A cross-sectional population-based cohort study of 1464 participants without overt cardiovascular disease was conducted. Dietary intake was assessed using a food frequency questionnaire. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), and the FADS1 locus variant was determined. Blood cell transcriptomics was performed in a subset of 410 individuals. Pulse wave velocity was significantly associated with the FADS1 locus variant. Differential associations between PWV and omega-3 PUFA intake were observed depending on the FADS1 genotype. High omega-3 PUFA intake attenuated the FADS1 genotype-dependent associations. Carriers of the minor FADS1 locus variant exhibited increased expression of FADS2, which is associated with PWV.CONCLUSION: Taken together, these findings point to FADS1 genotype-dependent associations of omega-3 PUFA intake on subclinical cardiovascular disease. These findings may have implications for identifying responders and non-responders to omega-3 PUFA supplementation and open up for personalized dietary counselling in cardiovascular prevention.
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| 3. |
- Plunde, Oscar, et al.
(författare)
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FADS1 (Fatty Acid Desaturase 1) Genotype Associates With Aortic Valve FADS mRNA Expression, Fatty Acid Content and Calcification
- 2020
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 2574-8300. ; 13:3, s. 139-148
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within theFADS1gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS.FADS1encodes a rate-limiting enzyme for omega-3 and omega-6 fatty acid metabolism. The aim of this study was to decipher the local transcriptomic and lipidomic consequences of rs174547 in tricuspid aortic valves from patients with AS. Methods: Expression quantitative trait loci study was performed using data from Illumina Human610-Quad BeadChip, Infinium Global Screening Arrays, and Affymetrix Human Transcriptome 2.0 arrays in calcified and noncalcified aortic valve tissue from 58 patients with AS (mean age, 74.2; SD, 5.9). Fatty acid content was assessed in aortic valves from 25 patients with AS using gas chromatography.Delta 5 and Delta 6 desaturase activity was assessed by the product-to-precursor ratio. Results: The minor C-allele of rs174547, corresponding to the protective genotype for AS, was associated with higher FADS2 mRNA levels in calcified valve tissue, whereas FADS1 mRNA and other transcripts in proximity of the single nucleotide polymorphism were unaltered. In contrast, the FADS1 Delta 5-desaturase activity and the FADS2 Delta 6-desaturase activity were decreased. Finally, docosahexaenoic acid was decreased in calcified tissue compared with non-calcified tissue and C-allele carriers exhibited increased docosahexaenoic acid levels. Overall desaturase activity measured with omega-3 fatty acids was higher in C-allele carriers. Conclusions: The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.
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| 4. |
- Plunde, Oscar
(författare)
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Pathways linking atherosclerosis to aortic stenosis
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease is the most common cause of death world-wide where atherosclerosis is the main culprit and aortic valve disease accounts about two percent of all CVD deaths. Atherosclerosis is a lipid and inflammation driven disease that share many features with aortic valve stenosis (AVS). Globally, the prevalence of AVS has been estimated to over 10 million patients and the incidence to over 12 500 new cases annually which is likely increasing due to increased longevity, yet no medical treatment is available. A link between atherosclerosis and AVS has previously been established by overlapping prevalence and common pathobiological hallmarks including lipid infiltration, inflammation, and calcification. Recent genetic studies have demonstrated several loci in which single nucleotide polymorphisms are associated with both diseases. However, there is also evidence pointing to separate etiologies including disease specific genetic risk factors, histopathological differences, and isolated clinical presentation. The aim of this thesis was to establish the interplay between atherosclerosis and AVS. A physiologic part was covered in Article I, specific mechanisms in Article II-IV and molecular epidemiology in Article IV. In Article I, arterial stiffness was determined in a cohort with ascending aortic dilatation and/or aortic valve disease before and after cardiac surgery. Arterial stiffness correlates with atherosclerotic cardiovascular disease and aggravates the increased left ventricular stress in AVS. Cardio-ankle vascular index (CAVI) measures arterial stiffness from the heart to the ankle and was lower in subjects with AVS compared with aortic regurgitation and ascending aortic dilation, before surgery, despite being older. In contrast, aortic stiffness assessed by carotid femoral pulse wave velocity (cfPWV) was not different between the groups. After surgery, CAVI but not cfPWV increased in patients with AVS but remained unchanged in patients undergoing aortic surgery. Age, diabetes, lower body mass index, decreased ejection time and lower preoperative CAVI was associated with an increased CAVI after surgery. The results suggest that AVS may mask an increased arterial stiffness if peripheral arteries are included in the measurement. Also, ejection time emerged as an important variable to account for when measuring arterial stiffness in aortic valve disease patients. Future work should aim to establish if arterial stiffness may be used to risk-stratify AVS patients. In Article II, the impact of a single nucleotide polymorphism (SNP) within FADS1 on aortic valve gene expression and fatty acid composition was identified. Fatty acid desaturase (FADS)1 and FADS2 encode rate limiting enzymes in the metabolism of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) and the SNP within this locus is associated with lower risk of both AVS and CAD. The SNP rs17547 was associated with FADS2 mRNA expression in calcified aortic valve tissue and the enzymatic activity of both FADS1 and FADS2. In addition, the aortic valve omega-3 PUFA docosahexaenoic acid proportion was higher in non-calcified compared with calcified tissue and positively correlated with the SNP. The results indicate that the protective effects of the SNP might be mediated via an increased DHA proportion in the aortic valve and/or possibly via downstream mediators from DHA such as specialized pro-resolving mediators which have been shown to dampen inflammation. Further pathophysiological evidence of shared pathways between CAD and AVS was obtained in Article III. The presence of antiphospholipid antibodies (aPL) in the general population is higher in patients with a recent myocardial infarction. Positivity for antibodies against β2-glycoprotein I and/or cardiolipin of IgG isotype was identified to be 8-fold higher in AVS patients compared with matched controls. In aortic valve tissue, aPL positivity was associated with downregulated interferon pathways and upregulated pathways related to mechanosensory signaling. Importantly, the differentially expressed genes could predict resilient (healthy), thickened (fibrotic) and calcified aortic valve tissue with high accuracy using supervised machine learning models suggesting a tight relationship between aPL related genes and local disease progression. The overall results imply that aPL IgG in the general population (without rheumatic disease) could be a risk factor for AVS and may potentially be used guide AVS precision medicine. In Article IV, CAD associated gene expression in aortic valve tissue was identified. First, the prevalence of CAD in a contemporary surgical tricuspid AVS cohort was established at 49% and was associated with claudication, smoking, male sex, and diabetes. An exploratory analysis of aortic valve transcriptomic data from 74 patients revealed that severe CAD, affecting 2 or 3 vessel territories, was associated with the most prominent difference in gene expression. The differentially expressed genes were primarily found in non-calcified tissue and were enriched in pathways related to oxidative stress, inflammation, and lipids. Furthermore, a supervised machine learning model could predict if aortic valve tissue stemmed from patients with severe CAD, at high accuracy. The most important gene predictors of severe CAD could further be used to predict atherosclerotic or macroscopically normal carotid artery tissue. The results suggest that AVS patients with concomitant severe CAD exhibit more atherosclerosis related mechanisms in non-calcified tissue, ultimately leading to a common end-stage disease with severe AVS. In summary, the results in this thesis demonstrate that AVS may be a cause of masked systemic arterial stiffness. Furthermore, pathways related to fatty acid metabolism and aPL are implicated in the pathophysiology of AVS and patients with severe CAD exhibit upregulated pathways related to atherosclerosis in the aortic valve. Collectively, pathways linking and differentiating aortic valve and vascular atherosclerotic disease were unraveled which open up for novel precision treatment regiments to halt AVS.
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| 5. |
- Sainz-Jaspeado, Miguel, et al.
(författare)
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Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium
- 2021
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 144:20, s. 1629-1645
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Tidskriftsartikel (refereegranskat)abstract
- Background: PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis 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, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, 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 single nucleotide polymorphism rs7543130 informed about gene regulatory changes.Results: ECs express the cytosolic PALMD-KKVI splice variant, which associated with RANGAP1 (RAN GTP hydrolyase activating protein 1). RANGAP1 regulates the activity of the GTPase RAN and thereby nucleocytoplasmic shuttling via XPO1 (Exportin1). 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 because of the effect on localization of transcriptional regulators. Changes in EC responsiveness on 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 patients with calcific aortic valve stenosis. 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 calcific aortic valve stenosis pathology.
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