Dataset Information

Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

ABSTRACT: 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.

SUBMITTER: Jung JJ

PROVIDER: S-EPMC5020643 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

Jung Jae-Joon JJ Razavian Mahmoud M Kim Hye-Yeong HY Ye Yunpeng Y Golestani Reza R Toczek Jakub J Zhang Jiasheng J Sadeghi Mehran M MM

Scientific reports 20160913

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, w ...[more]

PMID: 27619752

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Project description:Associative memory can be rendered malleable by a reminder. Blocking the ensuing reconsolidation process is suggested as a therapeutic target for unwanted aversive memories. Matrix metalloproteinase-9 (MMP-9) is required for structural synapse remodeling involved in memory consolidation. Inhibiting MMP-9 with doxycycline is suggested to attenuate human threat conditioning. Here, we investigated whether MMP-9 inhibition also interferes with threat memory reconsolidation. Male and female human participants (N = 78) learned the association between two visual conditioned stimuli (CS+) and a 50% chance of an unconditioned nociceptive stimulus (US), and between CS- and the absence of US. On day 7, one CS+ was reminded without reinforcement 3.5 h after ingesting either 200 mg of doxycycline or placebo. On day 14, retention of CS memory was assessed under extinction by fear-potentiated startle. Contrary to our expectations, we observed a greater CS+/CS- difference in participants who were reminded under doxycycline compared with placebo. Participants who were reminded under placebo showed extinction learning during the retention test, which was not observed in the doxycycline group. There was no difference between the reminded and the nonreminded CS+ in either group. In contrast, during relearning after the retention test, the CS+/CS- difference was more pronounced in the placebo group than in the doxycycline group. To summarize, a single dose of doxycycline before threat memory reminder appeared to have no specific impact on reconsolidation, but to globally impair extinction learning, and threat relearning, beyond drug clearance.SIGNIFICANCE STATEMENT Matrix metalloproteinase-9 inhibition appears to attenuate memory consolidation. It could also be a target for blocking reconsolidation. Here, we test this hypothesis in human threat conditioning. We find that doxycycline has no specific impact on a reminded cue, but confers a global reduction in extinction learning and threat learning beyond the clearance of the drug. This may point toward a more long-lasting impact of doxycycline treatment on memory plasticity.

Dataset Information

Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

Publications

Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

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