Effect of Trimethylamine N-Oxide on Interfacial Electrostatics at Phospholipid Monolayer-Water Interfaces and Its Relevance to Cardiovascular Disease

Jahur A. Mondal

Radiation & Photochemistry Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.


Background: Cardiovascular disease (CVD) which is the single largest cause of annual global death is associated with the progressive accumulation of fat (e.g. lipids, cholesterol, and macrophages) on the inner wall of arteries (endothelial membrane). Recently, it has been found that trimethylamine N-oxide (TMAO) – a metabolite of choline containing dietary nutrients which are abundant in red meat, egg, and other dietary supplements, enhances the arterial deposition of fat. The deposited fat makes the arteries harder and narrower and increases the risk of cardiovascular accidents (e.g. heart attack or stroke).

Objectives: The key early event behind the excess arterial deposition is the perturbation of the binding interaction between the artery wall and the cholesterol/fat carriers (low and high density lipoproteins; LDL and HDL). Electrostatics at the artery wall-blood interface and at the surface of LDL/HDL particle plays vital role in such interactions. We have investigated the effect of TMAO on the interfacial electrostatics at model endothelial membrane-blood Interface.

Methods: Selective probing of an interface e.g. membrane-water interface is challenging; because the conventional measurements are almost always accompanied by strong bulk signal. Here we have used an even-order nonlinear spectroscopy technique, heterodyne-detected vibrational sum frequency generation (HD-VSFG), which provides not only the interface-selective absorption characteristics of molecules but also their absolute orientations. The HD-VSFG measurement directly reveals the perturbation of electric field at model endothelial membrane-water interface in presence of TMAO.

Key Findings: The inner wall of artery which is mainly formed by the zwitterionic lipid, phosphatidylcholine, exhibits weak negative electric field at the interface. However, in the presence of TMAO (a net neutral zwitterionic molecule), there is a dramatic increase in the electric field (negative charge) at the artery wall. Controlled experiments reveled that TMAO increases the relative influence of the anionic phosphate by preferential screening of the cationic choline at the artery wall.

Significance: Elevated TMAO level in serum increases the negative electric filed at the endothelial membrane-blood interface (artery wall) and at the surface of LDL/HDL particles. The modified electrostatics affects the binding interaction of LDL/HDL with the artery wall, setting the stage for the pathogenesis of CVD.

PMID: 27096306


Figure 1 schematically illustrates the effect of TMAO on the interfacial electrostatics at the artery wall-blood interface. In the absence of TMAO (left panel), the interfacial electric field (E) is weak due to the net neutral (zwitterionic) headgroup of the artery wall forming lipid. However, in the presence of TMAO (right panel), the interfacial electric field (E) becomes strong, and the artery wall becomes effectively negatively charged. TAMO induced charging of the membrane interface is achieved by the preferential screening of the cationic choline over the anionic phosphate of the lipid.