Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms.
OBJECTIVE
Angiotensin II (AngII) infusion into hyperlipidemic mice leads to the rapid formation of atherosclerotic lesions and abdominal aortic aneurysms (AAAs). To define the role of matrix metalloproteinases (MMPs) in the development of these vascular pathologies, we administered the broad-spectrum MMP inhibitor doxycycline to saline- and AngII-infused LDL receptor-/- mice.


RESULTS
Mice were placed on a high-fat diet for 1 week before infusion with either saline or AngII (1000 ng x kg(-1) x min(-1)) via osmotic pumps for 28 days. Doxycycline (30 mg x kg(-1) x d(-1)) was administered in the drinking water to both saline- and AngII-infused mice. Administration of doxycycline did not significantly influence systolic blood pressure, serum cholesterol concentrations, or lipoprotein-cholesterol distribution. Doxycycline had no effect on the extent of atherosclerosis in saline- or AngII-infused mice. In contrast, doxycycline markedly reduced the incidence of AAA formation (86% vs 35%, AngII vs AngII+doxycycline, respectively; P<0.05), in addition to reducing aneurysm severity.


CONCLUSIONS
These data do not imply a role for MMPs in AngII-induced atherosclerosis but provide evidence consistent with a role in AngII-induced AAA formation.
Manning
Michael W
MW
Department of Physiology, University of Kentucky, Lexington, KY 40536-0230, USA.
Cassis
Lisa A
LA
Daugherty
Alan
A
D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism*; D001161:Arteriosclerosis / Q000139:chemically induced / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000139:chemically induced; D008074:Lipoproteins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains
D008074:Lipoproteins; D061965:Matrix Metalloproteinase Inhibitors; C030104:lipoprotein cholesterol; D000804:Angiotensin II; D002784:Cholesterol; D020782:Matrix Metalloproteinases; D004318:Doxycycline