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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 2

Deletion of MMP12 eliminates the male sex bias for arterial stiffening and atherosclerosis.

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Deletion of MMP12 eliminates the male sex bias for arterial stiffening a...
Male and female LDLR–/– MMP12+/+ and LDLR–/– MMP12–/– mice were fed a high-fat diet from 8 to 24 weeks before analysis. (A) Small portions of the descending aortas from the LDLR–/– and MMP12–/– LDLR–/– mice were analyzed by AFM (n = 4 for each group). The arrow indicates the median elastic modulus of a WT aorta (10). (B) Lipid-rich atherosclerotic lesions were identified by en face Oil Red O staining of isolated aortas from male LDLR–/– (n = 10) and LDLR–/– MMP12–/– (n = 14) mice and female LDLR–/– (n = 10) and LDLR–/– MMP12–/– (n = 11) mice. Scale bar: 1 mm. (C) Quantitation of results in B expressed as a percentage of the aortic area. The dot indicates a statistical outlier. (D) Blood cholesterol levels of male LDLR–/– (n = 9) and LDLR–/– MMP12–/– (n = 14) mice and female LDLR–/– (n = 10) and LDLR–/– MMP12–/– (n = 12) mice were determined at the time of sacrifice. 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. Statistical significance for all panels was determined by ANOVA.

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