Unsaturated Fatty Acids Drive Disintegrin and Metalloproteinase (ADAM)-dependent Cell Adhesion, Proliferation, and Migration by Modulating Membrane Fluidity

Abstract

The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers.

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

“…The analysis of the lipid composition of early valvular cusp lesions (grade 1) compared with internal control tissues by mass spectrometry detecting both unesterified cholesterol and linoleic acid corroborated our immunohistochemical findings. While it is known that free cholesterol has an intrinsic complement‐activating capacity (see later),28 free fatty acids contained in the eLDL particle not only bind and activate C129 but also play multifaceted roles through their dual capacity to exert stimulatory and cytotoxic effects on neighboring cells 14, 15…”

“…If the capacity of the system is overburdened (eg, hypercholesterolemia), accumulation of eLDL is the consequence with subsequent generation of potentially harmful C5b‐9 complexes by both the classic and the alternative pathway 12, 13. Further, free fatty acids contained in the eLDL particle play multifaceted roles through their dual capacity to exert stimulatory and cytotoxic effects on neighboring cells 14, 15. These findings suggest a crucial role for inflammation in the initiation of atherosclerosis, with emphasis on eLDL as one important causative component.…”

Renin-Angiotensin System Inhibitors Can Prevent Intravenous Lipid Infusion-Induced Myocardial Microvascular Dysfunction and Leukocyte Activation

“…6,7,9,29,31- 34 We found that FFA-induced myocardial microcirculation impairment was associated with elevated ological issues, although FFA-induced oxidative stress might cause erythrocyte crenation and slight hemolysis. 40, 41 Finally, leukocyte behavior in the human myocardial microcirculation could not be visualized due to methodological limitations.…”

Nutrigenomics and Atherosclerosis: The Postprandial and Long-Term Effects of Virgin Olive Oil Ingestion

“…ADAM-17 is a candidate gene of atherosclerosis susceptibility in mice models of atherosclerosis (Holdt et al, 2008), it mediates the release of several cell-signaling and cell adhesion molecules such as vascular endothelial (VE)-cadherin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) or L-selectin affecting endothelial permeability and leukocyte transmigration. According with this study, Reiss et al 2011, have recently show that unsaturated FFA increase ADAM-mediated substrate cleavage, with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. LLorent-Cortes et al 2010, have also concluded that a Mediterranean-type diet in a high-risk cardiovascular population impacts the expression of genes involved in inflammation, vascular foam cell formation and vascular remodelling in human monocytes.…”