bims-noxint 2019-07-14 papers

Issue of 2019‒07‒14
two papers selected by
Laia Caja Puigsubira
Uppsala University

Redox Biol. 2019 Jun 29. pii: S2213-2317(19)30274-5. [Epub ahead of print]26 101263

Protein tyrosine phosphatase 1b deficiency protects against hepatic fibrosis by modulating nadph oxidases.

Inmaculada García García-Ruiz, Nerea Blanes Ruiz, Patricia Rada, Virginia Pardo, Laura Ruiz, Ana Blas-García, M Pilar Valdecantos, Montserrat Grau Sanz, José A Solís Herruzo, Ángela M Valverde.

Inflammation is typically associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The key role of protein tyrosine phosphatase 1B (PTP1B) in inflammatory responses has focused this study in understanding its implication in liver fibrosis. Here we show that hepatic PTP1B mRNA expression increased after bile duct ligation (BDL), while BDL-induced liver fibrosis was markedly reduced in mice lacking Ptpn1 (PTP1B-/-) as assessed by decreased collagen deposition and α-smooth muscle actin (α-SMA) expression. PTP1B-/- mice also showed a significant increase in mRNA levels of key markers of monocytes recruitment (Cd68, Adgre1 and Ccl2) compared to their wild-type (PTP1B+/+) littermates at early stages of injury after BDL. Interestingly, the lack of PTP1B strongly increased the NADPH oxidase (NOX) subunits Nox1/Nox4 ratio and downregulated Cybb expression after BDL, revealing a pro-survival pattern of NADPH oxidase induction in response to liver injury. Chimeric mice generated by transplantation of PTP1B-/- bone marrow (BM) into irradiated PTP1B+/+ mice revealed similar hepatic expression profile of NOX subunits than PTP1B-/- mice while these animals did not show differences in infiltration of myeloid cells at 7 days post-BDL, suggesting that PTP1B deletion in other liver cells is necessary for boosting the early inflammatory response to the BDL. PTP1B-/- BM transplantation into PTP1B+/+ mice also led to a blockade of TGF-β and α-SMA induction after BDL. In vitro experiments demonstrated that deficiency of PTP1B in hepatocytes protects against bile acid-induced apoptosis and abrogates hepatic stellate cells (HSC) activation, an effect ameliorated by NOX1 inhibition. In conclusion, our results have revealed that the lack of PTP1B switches NOX expression pattern in response to liver injury after BDL and reduces HSC activation and liver fibrosis.

Keywords: Bile duct ligation; Bone marrow transplantation; Inflammation; Liver fibrosis; NADPH oxidases; Protein tyrosine phosphatase 1B

DOI: https://doi.org/10.1016/j.redox.2019.101263

Cardiovasc Res. 2019 Jul 11. pii: cvz183. [Epub ahead of print]

New opportunities for targeting redox dysregulation in cardiovascular disease.

Kristen J Bubb, Grant R Drummond, Gemma A Figtree.

Despite substantial promise, the use of antioxidant therapy to improve cardiovascular outcomes has been disappointing. Whilst the fundamental biology supporting their use continues to build, the challenge now is to differentially target dysregulated redox signaling domains and to identify new ways to deliver antioxidant substances. Looking further afield to other disciplines, there is an emerging 'tool-kit' containing sophisticated molecular and drug delivery applications. Applying these to the cardiovascular redox field could prove a successful strategy to combat the increasing disease burden. Excessive reactive oxygen species (ROS) production and protein modifications in the mitochondria has been the target of successful drug development with several positive outcomes emerging in the cardiovascular space, harnessing both improved delivery mechanisms and enhanced understanding of the biological abnormalities. Using this as a blueprint, similar strategies could be applied and expanded upon in other redox-hot-spots, such as the caveolae sub-cellular region, which houses many of the key cardiovascular redox proteins such as NADPH oxidase, endothelial nitric oxide synthase (eNOS), angiotensin II receptors and beta adrenoceptors. The expanded tool kit of drug development, including gene and miRNA therapies, nanoparticle technology and micropeptide targeting, can be applied to target dysregulated redox signaling in subcellular compartments of cardiovascular cells. In this review we consider the opportunities for improving cardiovascular outcomes by utilizing new technology platforms to target subcellular "bonfires" generated by dysregulated redox pathways, to improve clinical outcomes.

Keywords: biomarker; caveolae; drug development; reactive oxygen species; redox signaling

DOI: https://doi.org/10.1093/cvr/cvz183