Two articles from JCI about atherosclerosis
Note that JCI articles are free.
Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice
Evis Harja1, De-xiu Bu1, Barry I. Hudson1, Jong Sun Chang1, Xiaoping Shen1, Kellie Hallam1, Anastasia Z. Kalea1, Yan Lu1, Rosa H. Rosario1, Sai Oruganti1, Zana Nikolla1, Dmitri Belov1, Evanthia Lalla2, Ravichandran Ramasamy1, Shi Fang Yan1 and Ann Marie Schmidt1
1Division of Surgical Science, Department of Surgery, and
2College of Dental Medicine, Columbia University Medical Center, New York, New York, USA.
Address correspondence to: Ann Marie Schmidt, Division of Surgical Science, Department of Surgery, Columbia University Medical Center, 630 West 168th Street, P&S 17-501, New York, New York 10032, USA. Phone: (212) 305-6406; Fax: (212) 305-5337; E-mail: ams11@columbia.edu.
Published January 2, 2008
Received for publication May 16, 2007, and accepted in revised form October 24, 2007.
Abstract
Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE–/– mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.
J. Clin. Invest. 118: 183-194 (2007). doi:10.1172/JCI32703.
Copyright ©2007 by the American Society for Clinical Investigation
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Phospholipase C ß3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice
Zhenglong Wang1,2, Bei Liu3, Ping Wang1, Xuemei Dong1, Carlos Fernandez-Hernando1, Zhong Li2, Timothy Hla4, Zihai Li3, Kevin Claffey4, Jonathan D. Smith5 and Dianqing Wu1
1Program for Vascular Biology and Therapeutics and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
2Department of Genetics and Developmental Biology,
3Department of Immunology, and
4Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.
5Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Address correspondence to: Dianqing Wu, Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, Connecticut 06520-8066, USA. Phone: (203) 785-3149; Fax: (203) 737-1097; E-mail: dan.wu@yale.edu.
Published January 2, 2008
Received for publication June 29, 2007, and accepted in revised form October 17, 2007.
Abstract
Atherosclerosis is an inflammatory disease that is associated with monocyte recruitment and subsequent differentiation into lipid-laden macrophages at sites of arterial lesions, leading to the development of atherosclerotic plaques. PLC is a key member of signaling pathways initiated by G protein–coupled ligands in macrophages. However, the role of this enzyme in the regulation of macrophage function is not known. Here, we studied macrophages from mice lacking PLC ß2, PLC ß3, or both PLC isoforms and found that PLC ß3 is the major functional PLC ß isoform in murine macrophages. Although PLC ß3 deficiency did not affect macrophage migration, adhesion, or phagocytosis, it resulted in macrophage hypersensitivity to multiple inducers of apoptosis. PLC ß3 appeared to regulate this sensitivity via PKC-dependent upregulation of Bcl-XL. The significance of PLC ß signaling in vivo was examined using the apoE-deficient mouse model of atherosclerosis. Mice lacking both PLC ß3 and apoE exhibited fewer total macrophages and increased macrophage apoptosis in atherosclerotic lesions, as well as reduced atherosclerotic lesion size when compared with mice lacking only apoE. These results demonstrate what we believe to be a novel role for PLC activity in promoting macrophage survival in atherosclerotic plaques and identify PLC ß3 as a potential target for treatment of atherosclerosis.
J. Clin. Invest. 118: 195-204 (2007). doi:10.1172/JCI33139.
Copyright ©2007 by the American Society for Clinical Investigation
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