Opposing Effects on Vascular Smooth Muscle Cell Proliferation and Macrophage-induced Inflammation Reveal a Protective Role for the Proresolving Lipid Mediator Receptor ChemR23 in Intimal Hyperplasia

Artiach, Gonzalo; Carracedo, Miguel; Clària, Joan; Laguna-Fernández, Andrés; Bäck, Magnus

doi:10.3389/fphar.2018.01327

Cited by 23 publications

(24 citation statements)

References 20 publications

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“…In addition, previous studies had indicated a role of CmklR1 for the vascular smooth muscle cell (VSMC) atherosclerotic phenotype [47], characterized by vascular inflammation and intimal hyperplasia [48,49]. Surprisingly, chemerin seemed to inhibit atherogenesis through CmklR1 [48,50]. Carracedo et al [51] were able to show that chemerin treatment of isolated wild-type mouse VSMCs significantly reduced phosphate-induced calcification and increased expression of the calcification inhibitor matrix-gla-protein (MGP).…”

Section: Discussionmentioning

confidence: 99%

“…This seems controversial, as CKD induces premature vascular aging with vascular calcification and increased arterial stiffness [46]. In addition, previous studies had indicated a role of CmklR1 for the vascular smooth muscle cell (VSMC) atherosclerotic phenotype [47], characterized by vascular inflammation and intimal hyperplasia [48,49]. Surprisingly, chemerin seemed to inhibit atherogenesis through CmklR1 [48,50].…”

Section: Discussionmentioning

confidence: 99%

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Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

Mocker

Hilgers

Cordasic

et al. 2019

IJMS

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Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

Mocker

Hilgers

Cordasic

et al. 2019

IJMS

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“…RvE1 signals through ChemR23 34 and has been shown, for example, to reduce atherosclerosis 9 and intimal hyperplasia. 10 , 35 RvE1-induced effects on macrophages include decreasing inflammation, inhibiting oxidized low-density lipoprotein uptake, and increasing phagocytosis. 9 Those proresolving actions are stimulated by a macrophage polarization toward an M2-like or intermediate phenotype.…”

Section: Discussionmentioning

confidence: 99%

Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease Through the Resolvin E1 and ChemR23 Axis

et al. 2020

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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.

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“…At the end of the incubation periods, total VIC RNA was isolated as described above. Real-time PCR was performed on a 7900HT Fast RealTime PCR system (Perkin-Elmer Applied Biosystems, Norwalk, CT, USA) as previously described [19] using Taqman Assay-on-Demand (Thermo Fisher Scientific, Waltham, MA, USA) for PRG4 (Hs00981633_m1), BMP2 (Hs00154192_m1), RUNX2 (Hs00231692_m1). and SRY-Box transcription factor 9 (SOX9) (Hs00165814_m1).…”

Section: Valve Interstitial Cells (Vic) Treatments and Real-time Pcrmentioning

confidence: 99%

Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification

Artiach

Carracedo

Seime

et al. 2020

Cells

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Aortic valve stenosis (AVS), a consequence of increased fibrosis and calcification of the aortic valve leaflets, causes progressive narrowing of the aortic valve. Proteoglycans, structural components of the aortic valve, accumulate in regions with fibrosis and moderate calcification. Particularly, proteoglycan 4 (PRG4) has been identified in fibrotic parts of aortic valves. However, the role of PRG4 in the context of AVS and aortic valve calcification has not yet been determined. Here, transcriptomics, histology, and immunohistochemistry were performed in human aortic valves from patients undergoing aortic valve replacement. Human valve interstitial cells (VICs) were used for calcification experiments and RNA expression analysis. PRG4 was significantly upregulated in thickened and calcified regions of aortic valves compared with healthy regions. In addition, mRNA levels of PRG4 positively associated with mRNA for proteins involved in cardiovascular calcification. Treatment of VICs with recombinant human PRG4 enhanced phosphate-induced calcification and increased the mRNA expression of bone morphogenetic protein 2 and the runt-related transcription factor 2. In summary, PRG4 was upregulated in the development of AVS and promoted VIC osteogenic differentiation and calcification. These results suggest that an altered valve leaflet proteoglycan composition may play a role in the progression of AVS.

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Opposing Effects on Vascular Smooth Muscle Cell Proliferation and Macrophage-induced Inflammation Reveal a Protective Role for the Proresolving Lipid Mediator Receptor ChemR23 in Intimal Hyperplasia

Cited by 23 publications

References 20 publications

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease Through the Resolvin E1 and ChemR23 Axis

Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification

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