Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules.
Smoking is a significant risk factor for development of atherosclerosis. However, the pathophysiology of smoking-mediated vessel wall damage is not understood. With tools ranging from analytical chemistry to cell biology, we show that cigarette smoke contains metals that catalyze the direct oxidation of cellular proteins by smoke oxidants. Oxidation of cellular proteins causes a loss of microtubule function, culminating in microtubule depolymerization and proteasome-dependent degradation of alpha-tubulin. As a consequence of the microtubule collapse, cytoskeletal structures as well as intermediate filaments break down, leading finally to a contraction of vascular endothelial cells. We observed a smoke extract-induced, calpain-dependent degradation of the intracellular form of platelet-endothelial cell adhesion molecule 1/CD31, as well as a release of P-selectin/CD62P, IL-6, and IL-8 from endothelial cells into the supernatant. Increased levels of soluble CD62P and IL-6 are well known to be associated with smoking in humans. Increased permeability of the vascular endothelium is a crucial event in atherogenesis. This work highlights the compounds and mechanisms by which cigarette smoke induces leakiness of the vascular endothelium.
Vascular Biology Group, Division of Experimental Pathophysiology and Immunology, Department Biocenter, Innsbruck Medical University, Innsbruck, Austria. David.Bernhard@uibk.ac.at
David
D
Bernhard
Adam
A
Csordas
Blair
B
Henderson
Andrea
A
Rossmann
Michaela
M
Kind
Georg
G
Wick
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D002384:Catalysis; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008670:Metals / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism*; D018384:Oxidative Stress; D019007:P-Selectin / Q000032:analysis; D017239:Paclitaxel / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011506:Proteins / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D014404:Tubulin / Q000378:metabolism; D014661:Vasoconstriction
D000975:Antioxidants; D015850:Interleukin-6; D016209:Interleukin-8; D008670:Metals; D019007:P-Selectin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011506:Proteins; D012906:Smoke; D014404:Tubulin; D017239:Paclitaxel; D002118:Calcium; D000111:Acetylcysteine