Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.
Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Currently, there is no non-invasive medical therapy for CAVD. Matrix metalloproteinases (MMPs) are upregulated in CAVD and play a role in its pathogenesis. Here, we evaluated the effect of doxycycline, a nonselective MMP inhibitor on CAVD progression in the mouse. Apolipoprotein (apo)E(-/-) mice (n = 20) were fed a Western diet (WD) to induce CAVD. After 3 months, half of the animals was treated with doxycycline, while the others continued WD alone. After 6 months, we evaluated the effect of doxycycline on CAVD progression by echocardiography, MMP-targeted micro single photon emission computed tomography (SPECT)/computed tomography (CT), and tissue analysis. Despite therapeutic blood levels, doxycycline had no significant effect on MMP activation, aortic valve leaflet separation or flow velocity. This lack of effect on in vivo images was confirmed on tissue analysis which showed a similar level of aortic valve gelatinase activity, and inflammation between the two groups of animals. In conclusion, doxycycline (100 mg/kg/day) had no effect on CAVD progression in apoE(-/-) mice with early disease. Studies with more potent and specific inhibitors are needed to establish any potential role of MMP inhibition in CAVD development and progression.
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Jae-Joon
JJ
Jung
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Mahmoud
M
Razavian
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Hye-Yeong
HY
Kim
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Yunpeng
Y
Ye
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Reza
R
Golestani
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Jakub
J
Toczek
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Jiasheng
J
Zhang
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States.|VA Connecticut Healthcare System, West Haven, CT, United States.
Mehran M
MM
Sadeghi
D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000150:complications / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D002114:Calcinosis / Q000150:complications / Q000473:pathology; D059305:Diet, High-Fat; D018450:Disease Progression; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018093:Gelatinases / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008055:Lipids / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice
D001057:Apolipoproteins E; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D004318:Doxycycline