Arterial stiffening is a hallmark of aging and a cholesterol-independent risk factor for cardiovascular disease, but how and why arteries stiffen remain largely unknown. Preliminary studies presented here reveal new insights into the mechanisms of age-dependent arterial stiffening and its link to atherosclerosis. We show that arterial stiffening is accelerated in both apoE-null and LDLR-null mice and that this stiffening is associated with the expression of MMP12 in VSMCs and macrophages. Additionally, we show that the protective effect of gender on arterial stiffness and atherosclerosis in reproductive-age females is associated with an estrogen- mediated inhibition of macrophage MMP12 gene expression. Remarkably, deletion of MMP12 is sufficient to prevent arterial stiffening and eliminate the male gender bias for both arterial stiffening and atherosclerosis. Based on these data, we hypothesize that the links between aging, arterial stiffening, gender, and atherosclerosis can all be broken by blocking the expression or activity of MMP12. Additionally, we extend our recently published work concluding that Cox2 suppresses the expression of ECM genes, including collagen-I, and that this effect opposes arterial stiffening. We propose that Cox2 counteracts the stiffening effect of MMP12, and that the reciprocal effects of Cox2 and MMP12 play central roles in determining overall arterial stiffness. To test these hypotheses, we now propose three aims to: i) define the relationship between MMP12 and arterial stiffening in atherosclerosis, ii) establish the role of age, female gender and estrogen on arterial stiffness, MMP12 expression, and macrophage homing to vessel, and iii) study the functional interactions between Cox2 and MMP12 on arterial stiffening and atherosclerosis.

Public Health Relevance

Arterial stiffening is a hallmark of aging and a cholesterol-independent risk factor for cardiovascular disease, but how and why arteries stiffen remains largely unknown. Our data show that age-dependent arterial stiffening is accelerated in atherosclerosis and that this effect is suppressed by estrogen in females during their reproductive phase. We identify a gene and protein that controls arterial stiffening and show that the expression of this gene is inhibited by estrogen. This application has the overall goal of understanding how age-dependent arterial stiffening is accelerated in atherosclerosis, how this effect promotes disease progression, and how this stiffening is inhibited by female gender and estrogen.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG047373-01
Application #
8668406
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kohanski, Ronald A
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$410,017
Indirect Cost
$152,113
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104