Oxidant-induced inhibition of myocardial calcium-independent phospholipase A₂

Author： McHowat Jane Swift Luther Sarvazyan Narine

ISSN： 1530-7905

Source： Cardiovascular Toxicology, Vol.1, Iss.4, 2001-12, pp. : 309-316

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

We discovered the acute inhibition of myocardial phospholipase A₂ activity by micromolar concentrations of tert-butyl hydroperoxide and hydrogen peroxide. Specifically, freshly isolated adult rat cardiomyocytes were treated with the oxidants for 30 min, and phospholipase A₂ activity was assessed in cell subcellular fractions using (16:0, [³H]18:1) plasmenylcholine and phosphatidylcholine substrates in the absence or presence of calcium. Calcium-independent phospholipase A₂ activity was inhibited by approx 50% in both the cytosolic and membrane fractions by the oxidants. The inhibition of the phospholipase A₂ activity was concentration dependent and preceded detectable changes in cell viability as assessed by lactate dehydrogenase release and rod-shaped morphology. Taking into account that oxidized sn-2 fatty acyl groups must first be hydrolyzed by phospholipase A₂ to be repaired by glutathione peroxidase, we suggest that the observed inhibition of phospholipase A₂ activity by oxidants compromises the myocyte's ability to deal with lipid peroxidation. This conclusion was further validated by the experiments in which pretreatment with the calcium-independent phospholipase A₂ inhibitor bromoenol lactone exacerbated cardiotoxicity of tert-butyl hydroperoxide in myocyte cultures.