We previously found that homocysteine (Hcy) induced plasma membrane flip-flop, apoptosis, and necrosis in cardiomyocytes. Inactivation of flippase by Hcy induced membrane flip-flop, while apoptosis was induced via a NOX2-dependent mechanism. It has been suggested that S-adenosylhomocysteine (SAH) is the main causative factor in hyperhomocysteinemia (HHC)-induced pathogenesis of cardiovascular disease. Therefore, we evaluated whether the observed cytotoxic effect of Hcy in cardiomyocytes is SAH dependent. Rat cardiomyoblasts (H9c2 cells) were treated under different conditions: (1) non-treated control (1.5 nM intracellular SAH with 2.8 μM extracellular L -Hcy), (2) incubation with 50 μM adenosine-2,3-dialdehyde (ADA resulting in 83.5 nM intracellular SAH, and 1.6 μM extracellular L -Hcy), (3) incubation with 2.5 mM D, L -Hcy (resulting in 68 nM intracellular SAH and 1513 μM extracellular L -Hcy) with or without 10 μM reactive oxygen species (ROS)-inhibitor apocynin, and (4) incubation with 100 nM, 10 μM, and 100 μM SAH. We then determined the effect on annexin V/propodium iodide positivity, flippase activity, caspase-3 activity, intracellular NOX2 and p47(phox) expression and localization, and nuclear ROS production. In contrast to Hcy, ADA did not induce apoptosis, necrosis, or membrane flip-flop. Remarkably, both ADA and Hcy induced a significant increase in nuclear NOX2 expression. However, in contrast to ADA, Hcy additionally induced nuclear p47(phox) expression, increased nuclear ROS production, and inactivated flippase. Incubation with SAH did not have an effect on cell viability, nor on flippase activity, nor on nuclear NOX2-, p47phox expression or nuclear ROS production. HHC-induced membrane flip-flop and apoptosis in cardiomyocytes is due to increased Hcy levels and not primarily related to increased intracellular SAH, which plays a crucial role in nuclear p47(phox) translocation and subsequent ROS production.
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http://dx.doi.org/10.1007/s11010-011-0973-4 | DOI Listing |
Biophys Chem
January 2025
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia. Electronic address:
The rapid spread of antibiotic-resistant strains of bacteria has created an urgent need for new alternative antibiotic agents. Membrane disrupting antimicrobial peptides (AMPs): short amino acid sequences with bactericidal and fungicidal activity that kill pathogens by permeabilizing their plasma membrane may offer a solution for this global health crisis. Magainin 2 is an AMP secreted by the African clawed frog (Xenopus laevis) that is described as a toroidal pore former membrane disrupting AMP.
View Article and Find Full Text PDFJ Phys Chem Lett
December 2024
Frankfurt Institute for Advanced Studies, Ruth-Moufang-Straße 1, 60438 Frankfurt am Main, Germany.
Biophys J
November 2024
Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois. Electronic address:
Lipid compositional asymmetry across the leaflets of the plasma membrane is an ubiquitous feature in eukaryotic cells. How this asymmetry is maintained is thought to be primarily controlled by active transport of lipids between leaflets. This strategy is facilitated by the fact that long-tail phospholipids and sphingolipids diffuse through the lipid bilayer slowly-taking many hours or days.
View Article and Find Full Text PDFChem Phys Lipids
November 2024
Department of Pharmacy, Uppsala University, Uppsala 751 23, Sweden. Electronic address:
The stratum corneum (SC) plays the most important role in the absorption of topical and transdermal drugs. In this study, we developed a multi-layered SC model using coarse-grained molecular dynamics (CGMD) simulations of ceramides, cholesterol, and fatty acids in equimolar proportions, starting from two different initial configurations. In the first approach, all ceramide molecules were initially in the hairpin conformation, and the membrane bilayers were pre-formed.
View Article and Find Full Text PDFJ Am Chem Soc
October 2024
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
In a recent study, spectroscopic observations of modified cholesterol in both lipid-coated nanoparticles and liposomes provided evidence for a disorder-to-order orientational transition with increasing temperature. Below a critical temperature, in a membrane composed of modified cholesterol, saturated (DPPC) lipid, and anionic (DOPS) lipid, a roughly equal population of head-out and head-in conformations was observed. Surprisingly, as temperature was increased the modified cholesterol presented an abrupt transition to a population of all head-in orientations.
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