IMPACT OF S-ADENOSYL HOMOCYSTEINE ON ENDOTHELIAL HOMEOSTASIS: POTENTIAL ROLE OF PI3K/AKT/FOXO SIGNALLING PATHWAYS

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Endothelial aquaporins and hypomethylation potential implications for atherosclerosis and cardiovascular disease

Publication . Silva, Inês Vieira da; Barroso, Madalena; Moura, Teresa; Castro, Rita; Soveral, Graça; DQ - Departamento de Química; MDPI - Multidisciplinary Digital Publishing Institute

Aquaporins (AQPs) are transmembrane channels that facilitate water and glycerol permeation through cell membranes. Recently, the water channel AQP1 was suggested to contribute to endothelial homeostasis and cardiovascular health. Less is known about endothelial aquaglyceroporins expression and its implication in cardiovascular disease (CVD). We have previously used cultured human endothelial cells under a hypomethylating environment to study endothelial dysfunction and activation, a phenotype implicated in the establishment of atherosclerosis and CVD. Here, we used the same cell model to investigate aquaporin’s expression and function in healthy or pro-atherogenic phenotype. We first confirmed key features of endothelium dysfunction and activation in our cell model, including an augmented endothelial transmigration under hypomethylation. Subsequently, we found AQP1 and AQP3 to be the most predominant AQPs accounting for water and glycerol fluxes, respectively, in the healthy endothelium. Moreover, endothelial hypomethylation led to decreased levels of AQP1 and impaired water permeability without affecting AQP3 and glycerol permeability. Furthermore, TNF-α treatment-induced AQP1 downregulation suggesting that the inflammatory NF-κB signaling pathway mediates AQP1 transcriptional repression in a pro-atherogenic endothelium, a possibility that warrants further investigation. In conclusion, our results add further support to AQP1 as a candidate player in the setting of endothelial dysfunction and CVD.

2018-01-01Artigo científico

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Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression

Publication . Barroso, Madalena; Florindo, Cristina; Kalwa, Hermann; Silva, Zélia; Turanov, Anton A.; Carlson, Bradley A.; De Almeida, Isabel Tavares; Blom, Henk J.; Gladyshev, Vadim N.; Hatfield, Dolph L.; Michel, Thomas; Castro, Rita; Loscalzo, Joseph; Handy, Diane E.; Centro de Estudos de Doenças Crónicas (CEDOC); NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); ASBMB - American Society for Biochemistry and Molecular Biology

Background: Methylation of tRNASec facilitates the incorporation of selenocysteine at a UGA codon during translation. Results: Accumulation of the homocysteine precursor S-adenosylhomocysteine decreases tRNASec methylation, reducing glutathione peroxidase 1 expression and increasing oxidative stress-induced inflammatory activation of endothelial cells. Conclusion: Methylation modulates the expression of selenoproteins to regulate redox-dependent inflammatory pathways. Significance: Hypomethylation stress promotes a proatherogenic endothelial cell phenotype.

2014-05-30Artigo científico

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/73021/2010