Trisulfate disaccharide decreases calcium overload and protects liver injury secondary to liver ischemia/reperfusion

Vasques, ER; Cunha, JEM; Coelho, AMM; Sampietre, SN; Patzina, RA; Abdo, EE; Nader, HB; Tersariol, ILS; Andrade De Lima, M; Godoy, CMG; Rodrigues, Tiago; Chaib, Eleazar; D’Albuquerque, Luiz A.C.

Abstract

Background
Ischemia and reperfusion (I/R) causes tissue damage and intracellular calcium levels are a factor of cell death. Sodium calcium exchanger (NCX) regulates calcium extrusion and Trisulfated Disaccharide (TD) acts on NCX decreasing intracellular calcium through the inhibition of the exchange inhibitory peptide (XIP).

Objectives
The aims of this research are to evaluate TD effects in liver injury secondary to I/R in animals and in vitro action on cytosolic calcium of hepatocytes cultures under calcium overload.

Methods
Wistar rats submitted to partial liver ischemia were divided in groups: Control: (n = 10): surgical manipulation with no liver ischemia; Saline: (n = 15): rats receiving IV saline before reperfusion; and TD: (n = 15): rats receiving IV TD before reperfusion. Four hours after reperfusion, serum levels of AST, ALT, TNF-a, IL-6, and IL-10 were measured. Liver tissue samples were collected for mitochondrial function and malondialdehyde (MDA) content. Pulmonary vascular permeability and histologic parameters of liver were determined. TD effect on cytosolic calcium was evaluated in BRL3A hepatic rat cell cultures stimulated by thapsigargin pre and after treatment with TD.

Results
AST, ALT, cytokines, liver MDA, mitochondrial dysfunction and hepatic histologic injury scores were less in TD group when compared to Saline Group (p<0.05) with no differences in pulmonary vascular permeability. In culture cells, TD diminished the intracellular calcium raise and prevented the calcium increase pre and after treatment with thapsigargin, respectively.

Conclusion
TD decreases liver cell damage, preserves mitochondrial function and increases hepatic tolerance to I/R injury by calcium extrusion in Ca2+ overload situations.

• Journal Article Type: Article
• Acceptance Date: Feb 3, 2016
• Publication Date: Feb 22, 2016
• Journal: PLoS ONE
• Print ISSN: 1932-6203
• Publisher: Public Library of Science
• Volume: 11
• Pages: e0149630--e0149630
• DOI: https://doi.org/10.1371/journal.pone.0149630
• Keywords: Mitochondria; reperfusion; disaccharides; histology; heparin; inflammation; liver transplantation; ischemia
• Publisher URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149630