Abstract
To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-α-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC 50values = 6, 10, and 25 μM, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.
Footnotes
-
↵ 1 Current address: Reddy US Therapeutics, Inc., Norcross, GA 30071.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
DOI: 10.1124/jpet.102.048132.
-
This work was supported by AtheroGenics, Inc. (Alpharetta, GA).
-
ABBREVIATIONS: ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; CAD, coronary artery disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein; AGI-1067, mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester; HDL, HDL cholesterol; LDLr -/-mice, LDL receptor-deficient mice; ApoE -/-mice, apolipoprotein E-deficient mice; LPS, lipopolysaccharide; ELISA, enzyme-linked immunosorbent assay; ICAM-1, intercellular adhesion molecule-1; HAECs, human aortic endothelial cells; TNF-α, tumor necrosis factor-α; HBSS, Hanks balanced salts solution; PBS, phosphate-buffered saline; LDLc, LDL cholesterol; HDLc, HDL cholesterol.
- Received December 13, 2002.
- Accepted February 24, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|