Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia-Reperfusion Injury

Abstract

Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.

Keywords: ischemia/reperfusion; kidney; lipidomics; liver.

Figure 1

The chain of metabolic events that accompany I/R injury. Na⁺/Ca²⁺—Na⁺/Ca²⁺ electrogenic exchanger (NCX); ROS—reactive oxygen species; mPTP—mitochondrial inner membranes permeability transition pores.

Figure 2

The summarized effects of meldonium on the hepatic and renal ischemia/reperfusion. p-Nrf2—phosphorylated nuclear factor erythroid 2-related factor 2; HO-1—haem oxygenase; HMGB1—high mobility group Box 1 protein; p-NF-kB p65—phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells; BAX—pro-apoptotic member of Bcl2 gene family; Bcl2—anti-apoptotic member of Bcl2 gene family. Upward pointing arrow (↑) indicates an increase, downward pointing arrow (↓) indicates a decrease, and NA indicates no changes.