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Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12
Shu-lin Liu, … , Kara L. Spiller, Richard K. Assoian
Shu-lin Liu, … , Kara L. Spiller, Richard K. Assoian
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e122742. https://doi.org/10.1172/jci.insight.122742.
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Research Article Cell biology Vascular biology

Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12

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Abstract

Arterial stiffening is a consequence of aging and a cholesterol-independent risk factor for cardiovascular disease (CVD). Arterial stiffening and CVD show a sex bias, with men more susceptible than premenopausal women. How arterial stiffness and sex interact at a molecular level to confer risk of CVD is not well understood. Here, we used the sexual dimorphism in LDLR-null mice to show that the protective effect of female sex on atherosclerosis is linked to reduced aortic stiffness and reduced expression of matrix metalloproteinase-12 (MMP12) by lesional macrophages. Deletion of MMP12 in LDLR-null mice attenuated the male sex bias for both arterial stiffness and atherosclerosis, and these effects occurred despite high serum cholesterol. Mechanistically, we found that oxidized LDL stimulates secretion of MMP12 in human as well as mouse macrophages. Estrogen antagonizes this effect by downregulating MMP12 expression. Our data support cholesterol-independent causal relationships between estrogen, oxidized LDL–induced secretion of macrophage MMP12, and arterial stiffness that protect against atherosclerosis in females and emphasize that reduced MMP12 functionality can confer atheroprotection to males.

Authors

Shu-lin Liu, Anamika Bajpai, Elizabeth A. Hawthorne, Yongho Bae, Paola Castagnino, James Monslow, Ellen Puré, Kara L. Spiller, Richard K. Assoian

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Figure 4

Estrogen inhibits MMP12 gene expression and secreted MMP12 in human Mox macrophages.

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Estrogen inhibits MMP12 gene expression and secreted MMP12 in human Mox ...
(A) Schematic of the experimental design. Female human peripheral blood–derived monocytes (PBDMs) were differentiated into M0 macrophages, treated with oxidized LDL (oxLDL), and exposed to selected concentrations of E2 as described in Methods. (B and C) Effect of oxLDL on the amount of secreted MMP12 and MMP12 mRNA, respectively, in M0 versus Mox macrophages (n = 7 per condition), with statistical significance determined by Mann-Whitney test. (D and E) Effect of E2 treatment on the amount of secreted MMP12 and MMP12 mRNA, respectively, in Mox macrophages (n = 7 per condition) with statistical significance determined by ANOVA. B–E show results from experiments that contained all conditions but are separated here to better emphasize distinct points; Mox samples lacking E2 in B and C are therefore the Mox samples without E2 in D and E. (F) Effect of E2 treatment on MMP12 mRNA levels in human SMCs stimulated with 20% FBS (n = 4). The arrow indicates the MMP12 mRNA level in the serum-starved cells before FBS treatment. Statistical significance was determined by ANOVA. Graphs show box-and-whisker plots with Tukey’s whiskers; the horizontal lines of boxes represent the 25th percentile, the median, and the 75% percentile.

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