Lateral transport of domains in anionic lipid bilayer membranes under DC electric fields: A coarse-grained molecular dynamics study

Dynamic lateral transport of lipids, proteins, and self-assembled structures in biomembranes plays crucial roles in diverse cellular processes. In this study, we perform a coarse-grained molecular dynamics simulation on a vesicle composed of a binary mixture of neutral and anionic lipids to investigate the lateral transport of individual lipid molecules and the self-assembled lipid domains upon an applied direct current (DC) electric field. Under the potential force of the electric field, a phase-separated domain rich in the anionic lipids is trapped in the opposite direction of the electric field. The subsequent reversal of the electric field induces the unidirectional domain motion. During the domain motion, the domain size remains constant, but a considerable amount of the anionic lipids is exchanged between the anionic-lipid-rich domain and the surrounding bulk. While the speed of the domain motion (collective lipid motion) shows a significant positive correlation with the electric field strength, the exchange of anionic lipids between the domain and bulk (individual lipid motion) exhibits no clear correlation with the field strength. The mean velocity field of the lipids surrounding the domain displays a two-dimensional (2D) source dipole. We revealed that the balance between the potential force of the applied electric field and the quasi-2D hydrodynamic frictional force well explains the dependence of the domain motions on the electric-field strengths. The present results provide insight into the hierarchical dynamic responses of self-assembled lipid domains to the applied electric field and contribute to controlling the lateral transportation of lipids and membrane inclusions.Comment: 9 pages, 6 figure

Coupling between pore formation and phase separation in charged lipid membranes

We investigated the effect of charge on the membrane morphology of giant unilamellar vesicles (GUVs) composed of various mixtures containing charged lipids. We observed the membrane morphologies by fluorescent and confocal laser microscopy in lipid mixtures consisting of a neutral unsaturated lipid [dioleoylphosphatidylcholine (DOPC)], a neutral saturated lipid [dipalmitoylphosphatidylcholine (DPPC)], a charged unsaturated lipid [dioleoylphosphatidylglycerol (DOPG$^{\scriptsize{(-)}}$)], a charged saturated lipid [dipalmitoylphosphatidylglycerol (DPPG$^{\scriptsize{(-)}}$)], and cholesterol (Chol). In binary mixtures of neutral DOPC/DPPC and charged DOPC/DPPG$^{\scriptsize{(-)}}$, spherical vesicles were formed. On the other hand, pore formation was often observed with GUVs consisting of DOPG$^{\scriptsize{(-)}}$ and DPPC. In a DPPC/DPPG$^{\scriptsize{(-)}}$/Chol ternary mixture, pore-formed vesicles were also frequently observed. The percentage of pore-formed vesicles increased with the DPPG$^{\scriptsize{(-)}}$ concentration. Moreover, when the head group charges of charged lipids were screened by the addition of salt, pore-formed vesicles were suppressed in both the binary and ternary charged lipid mixtures. We discuss the mechanisms of pore formation in charged lipid mixtures and the relationship between phase separation and the membrane morphology. Finally, we reproduce the results seen in experimental systems by using coarse-grained molecular dynamics simulations.Comment: 34 pages, 10 figure

Management of Coronary Artery Spasm

Calcium channel blockers (CCBs) are the first-line treatment for coronary artery spasm (CAS). When CAS-related angina symptoms are not well controlled by CCB therapy, long-acting nitrates or (where available) nicorandil can be added as second-line medications. In the case of CAS refractory to standard treatments, several other alternative drugs and interventions have been proposed, including the Rho-kinase inhibitor fasudil, anti-adrenergic drugs, neural therapies and percutaneous coronary interventions. In patients with syncope or cardiac arrest caused by CAS-related tachyarrhythmias, or even bradyarrhythmias, implantation of an ICD or pacemaker, respectively, should be considered according to the risk of recurrence and efficacy of vasodilator therapy

Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rho-kinase pathway

Objective: Pulsatile forces regulate vascular remodeling and trigger vascular diseases such as saphenous vein graft disease. The saphenous vein is exposed to high pressure and pulsatility only after implantation. Statins have been proved to reduce the incidence of vein graft failure. Thus, we investigated the molecular mechanisms of pulsatile stretch-induced saphenous vein smooth muscle cell (SMC) proliferation and potential beneficial effects of statins. Methods and results: Human saphenous vein SMCs were subjected to cyclic stretch (60 cycles/min) in Flex I plates. Cerivastatin and simvastatin significantly prevented stretch-induced increase in SMC proliferation. Stretch induced the membrane accumulation of Rho A and Rho kinase inhibitors (Y-27632 and hydroxyfasudil) and dominant negative Rho A mutant significantly prevented stretch-induced SMC proliferation. In addition, stretch increased the levels of both p44/42 mitogen-activated protein (MAP) kinase and Akt phosphorylation. MAP kinase kinase (MEK)1/2 inhibitor U0126, phosphatidylinositol (PI) 3-kinase inhibitors (wortmaninn and LY294002), and dominant negative Akt mutant significantly prevented stretch-induced SMC proliferation. Cerivastatin significantly prevented stretch-induced membrane accumulation of Rho A. On the other hand, stretch-induced phosphorylation of p44/42 MAP kinase and Akt was not prevented by cerivastatin. Mevalonate restored the preventive effect of cerivasatain on stretch-induced Rho A membrane accumulation. Stretch induced hyperphosphorylation of retinoblastoma protein (pRb), which was prevented by cerivastatin and the Rho kinase inhibitors. Conclusion: Statins prevent stretch-induced saphenous vein SMC proliferation via inhibition of the Rho/Rho-kinase pathway. This may explain the beneficial effects of this class of drug, especially for patients after coronary artery bypass graftin

Coronary Artery Spasm and Perivascular Adipose Tissue Inflammation: Insights From Translational Imaging Research

Perivascular adipose tissue, which constitutes perivascular components along with the adventitial vasa vasorum, plays an important role as a source of various inflammatory mediators in cardiovascular disease. Inflammatory changes in the coronary adventitia are thought to be involved in the pathogenesis of coronary artery spasm and vasospastic angina. Recent advances in translational research using non- invasive imaging modalities, including 18F-fluorodeoxyglucose PET and cardiac CT, have enabled us to visualise perivascular inflammation in the pathogenesis of coronary artery spasm. These modality approaches appear to be clinically useful as a non-invasive tool for examining the presence and severity of vasospastic angina