# Membrane Deformation and Mechanism of Stimulation of Phospholipase A2 by Oxidized Lipids

> **NIH NIH SC3** · CALIFORNIA STATE UNIVERSITY NORTHRIDGE · 2021 · $108,750

## Abstract

The focus of this project is the biophysical characterization of mixed assemblies of oxidized phospholipids
(OxPL) and heart and brain phosphatidylcholine (PC) lipids in Aim 1 and elucidation of the mechanism of OxPL
induced human group V (hgV) and group IIa (hgIIa) secretory phospholipase A2 (sPLA2) activity in Aim 2.
Published work and preliminary Laurdan emission spectroscopy on mixtures of OxPL and bilayer PL show lipid
compositional ordering in the form of OxPL rich domains or micelles and bilayer PL rich domains or vesicles.
A physicochemical basis for demixing is hypothesized to be (i) the hydrogen bond mediated bonding between
one OxPL polar terminal group and another OxPL ester group which brings the OxPL together to form OxPL
rich domains; (ii) the molecular shape difference between the inverse cone shaped OxPL and the conical
bilayer lipid which induces positive curvature in the OxPL domains and negative curvature in the bilayer PL
domains respectively. Curvature stresses eventually lead to separation of the OxPL rich domains as micelles.
Temperature and lipid unsaturation increase the bilayer cone angle because of increased chain mobility and
further accentuate the shape difference and promote demixing. Mixtures of the OxPL 1-palmitoyl-2-glutaryl-sn-
glycero-3-phosphocholine (carboxyl terminal group) and 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-
phosphocholine (aldehyde terminal group) and heart and brain PC lipids will be investigated by Dynamic Light
Scattering (DLS) for aggregate sizes and by Laurdan fluorescence to detect segregation. States of mixing
predicted are: homogenous mixing, bilayer with OxPL and bilayer PL rich domains, coexisting bilayer lipid
vesicles and OxPL micelles. Micelle / vesicle coexistence is readily detected by DLS, but mixed bilayers with
segregated domains are reported simply as vesicles. Using the sensitivity of Laurdan fluorescence excitation
and emission to inter-lipid bonding in domains and deconvolution using lognormal distributions will be novel
approaches to better detect domains. The hypothesis predicts that demixing will be more pronounced when
the terminal group is the more polar carboxyl rather than aldehyde. Membrane oxidation is known to be a
leading cause in triggering proinflammatory sPLA2 activity. Segregation stimulates enzymatic activity because
the high curvature OxPL domains or micelles are highly accessible substrates. The end group in the truncated
tail of OxPL is hydrophilic and points to the interface making the lipid protrude, further increasing its
accessibility. HgV sPLA2 hydrolyzes PC membranes and increases in its activity for these reasons. The hgIIA
sPLA2 does not bind to and does not hydrolyze PC membranes. However interfacial presence of charged
truncated tail end groups of OxPL creates a charged interface, to which this enzyme can bind, and stimulate
hydrolysis. The present research using pure PC bilayers will resolve the question of whether OxPL stimulates
sPLA2 irre...

## Key facts

- **NIH application ID:** 10140370
- **Project number:** 5SC3GM122499-04
- **Recipient organization:** CALIFORNIA STATE UNIVERSITY NORTHRIDGE
- **Principal Investigator:** Radha Ranganathan
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $108,750
- **Award type:** 5
- **Project period:** 2018-05-02 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140370

## Citation

> US National Institutes of Health, RePORTER application 10140370, Membrane Deformation and Mechanism of Stimulation of Phospholipase A2 by Oxidized Lipids (5SC3GM122499-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140370. Licensed CC0.

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