Anja Hofmann1, Coy Brunssen1, David M Poitz2, Heike Langbein1, Ruth H Strasser2, Thomas Henle3, Ursula Ravens4, Henning Morawietz5. 1. Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Medical Faculty Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany. 2. Department of Internal Medicine and Cardiology at the Technische Universität Dresden, Dresden, Germany. 3. Institute of Food Chemistry, Technische Universität Dresden, Dresden, Germany. 4. Department of Physiology, Medical Faculty Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; Institute of Experimental Cardiovascular Medicine, University Heart Centre Freiburg Bad Krozingen, Freiburg I. Br., Germany. 5. Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Medical Faculty Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany. Electronic address: Henning.Morawietz@tu-dresden.de.
Abstract
OBJECTIVE: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date. METHODS: Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr-/-) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph. RESULTS: WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P < 0.0001) in bLOX-1tg and WT mice without HDL-elevation in bLOX-1tg mice. Gonadal fat pad weight was 1.7 and 1.2-fold increased on CD and WD in bLOX-1tg mice compared to WT. LOX-1 overexpression impaired endothelial function by 15-16% (P < 0.05) on CD and WD. Crossing bLOX-1tg mice into Ldlr-/- background strongly elevated total (∼6-fold) and LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr-/- mice (Effmax: 56.7 ± 23.0%) compared to WT (Effmax: 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Effmax: 76.7 ± 12.9%, P < 0.05) and Ldlr-/- mice (Effmax: 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr-/- mice were detectable when comparing all genotypes. CONCLUSION: Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis.
OBJECTIVE: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date. METHODS:Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr-/-)mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph. RESULTS:WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P < 0.0001) in bLOX-1tg and WT mice without HDL-elevation in bLOX-1tg mice. Gonadal fat pad weight was 1.7 and 1.2-fold increased on CD and WD in bLOX-1tg mice compared to WT. LOX-1 overexpression impaired endothelial function by 15-16% (P < 0.05) on CD and WD. Crossing bLOX-1tg mice into Ldlr-/- background strongly elevated total (∼6-fold) and LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr-/- mice (Effmax: 56.7 ± 23.0%) compared to WT (Effmax: 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Effmax: 76.7 ± 12.9%, P < 0.05) and Ldlr-/- mice (Effmax: 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr-/- mice were detectable when comparing all genotypes. CONCLUSION: Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis.
Authors: Roman N Rodionov; Natalia Jarzebska; Dmitrii Burdin; Vladimir Todorov; Jens Martens-Lobenhoffer; Anja Hofmann; Anne Kolouschek; Nada Cordasic; Johannes Jacobi; Elena Rubets; Henning Morawietz; John F O'Sullivan; Alexander G Markov; Stefan R Bornstein; Karl Hilgers; Renke Maas; Christian Pfluecke; YingJie Chen; Stefanie M Bode-Böger; Christian P M Hugo; Bernd Hohenstein; Norbert Weiss Journal: Sci Rep Date: 2022-06-07 Impact factor: 4.996