Doxycycline stabilizes vulnerable plaque via inhibiting matrix metalloproteinases and attenuating inflammation in rabbits.
Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, China.
Mei
M
Dong
Lin
L
Zhong
Wen Qiang
WQ
Chen
Xiao Ping
XP
Ji
Mei
M
Zhang
Yu Xia
YX
Zhao
Li
L
Li
Gui Hua
GH
Yao
Peng Fei
PF
Zhang
Cheng
C
Zhang
Lei
L
Zhang
Yun
Y
Zhang
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000473:pathology; D004318:Doxycycline / Q000097:blood / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D008055:Lipids / Q000097:blood; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D014463:Ultrasonography / Q000379:methods
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases; D004318:Doxycycline