Reversal of myofibroblastic activation by polyunsaturated fatty acids in valvular interstitial cells from aortic valves. Role of RhoA/G-actin/MRTF signalling

Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin.

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Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

International Journal of Molecular Sciences ◽

10.3390/ijms22094356 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4356

Author(s):

Eva Knuplez ◽

Eva Maria Sturm ◽

Gunther Marsche

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Critical Role ◽

Allergic Inflammation ◽

Lipid Mediators ◽

Comprehensive Overview ◽

Local Immunity ◽

Effector Cells ◽

Inflammatory Phenotype

Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.

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Role of n-3 Polyunsaturated Fatty Acids and Exercise in Breast Cancer Prevention: Identifying Common Targets

Nutrition and Metabolic Insights ◽

10.4137/nmi.s39043 ◽

2016 ◽

Vol 9 ◽

pp. NMI.S39043 ◽

Cited By ~ 7

Author(s):

Salma A. Abdelmagid ◽

Jessica L. MacKinnon ◽

Sarah M. Janssen ◽

David W.L. Ma

Keyword(s):

Breast Cancer ◽

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Cancer Prevention ◽

Breast Cancer Prevention ◽

Future Research ◽

Pufa Intake ◽

Diet And Exercise ◽

Important Study

Diet and exercise are recognized as important lifestyle factors that significantly influence breast cancer risk. In particular, dietary n-3 polyunsaturated fatty acids (PUFAs) have been shown to play an important role in breast cancer prevention. Growing evidence also demonstrates a role for exercise in cancer and chronic disease prevention. However, the potential synergistic effect of n-3 PUFA intake and exercise is yet to be determined. This review explores targets for breast cancer prevention that are common between n-3 PUFA intake and exercise and that may be important study outcomes for future research investigating the combined effect of n-3 PUFA intake and exercise. These lines of evidence highlight potential new avenues for research and strategies for breast cancer prevention.

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Maternal Malnutrition in the Etiopathogenesis of Psychiatric Diseases: Role of Polyunsaturated Fatty Acids

Brain Sciences ◽

10.3390/brainsci6030024 ◽

2016 ◽

Vol 6 (3) ◽

pp. 24 ◽

Cited By ~ 16

Author(s):

Maria Morgese ◽

Luigia Trabace

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Psychiatric Diseases ◽

Maternal Malnutrition

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Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20061486 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1486 ◽

Cited By ~ 6

Author(s):

Miguel Carracedo ◽

Oscar Persson ◽

Peter Saliba-Gustafsson ◽

Gonzalo Artiach ◽

Ewa Ehrenborg ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Valve Stenosis ◽

Interstitial Cells ◽

Left Ventricular ◽

Autophagic Flux ◽

Valvular Interstitial Cells ◽

Survival Mechanism ◽

Calcified Tissue ◽

Left Ventricular Outflow

Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age. Currently, no medical treatment exists for CAVS, and the role of autophagy in the disease remains largely unexplored. To further understand the role of autophagy in the progression of CAVS, we analyzed expression of key autophagy genes in healthy, thickened, and calcified valve tissue from 55 patients, and compared them with nine patients without significant CAVS, undergoing surgery for aortic regurgitation (AR). This revealed a upregulation in autophagy exclusively in the calcified tissue of CAVS patients. This difference in autophagy between CAVS and AR was explored by LC3 lipidation in valvular interstitial cells (VICs), revealing an upregulation in autophagic flux in CAVS patients. Inhibition of autophagy by bafilomycin-A1 led to a decrease in VIC survival. Finally, treatment of VICs with high phosphate led to an increase in autophagic activity. In conclusion, our data suggests that autophagy is upregulated in the calcified tissue of CAVS, serving as a compensatory and pro-survival mechanism.

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