Both low and high body mass indexes (BMI) are associated with the increased risk of coronary heart disease (CHD) and death. The molecular mechanism that underlies the deadly link, however, remains the subject of considerable speculation. Our long-term objective is to understand the role of the genetic program of tissue remodeling in regulating the association between adiposity and CHD. MMP14 encodes a membrane-type matrix metalloproteinase (MMP) that plays the major role in the physiological remodeling of extracellular matrix (ECM). MMP14 gene reduction (haploinsufficiency) renders mice resistant to high-fat diet induced ECM remodeling and gene expression. Unexpectedly, however, these leaner mice display inflammatory adipose tissue profile and aggravated atherosclerosis in ApoE knockout background. Our central hypothesis is that, under atherogenic nutritional challenge, enhanced MMP14 gene expression is required to maintain anti-fibrotic and anti-inflammatory states of adipose tissues and vascular walls. To test this central hypothesis, we propose the following two specific aims in this R21 mechanism. #1: Determine the role of MMP14 expressed by adipocytes in regulating systemic inflammation and atherosclerosis, and #2: Determine the role of MMP14 expressed by vascular smooth muscle cells in regulating vascular wall remodeling, inflammation and atherosclerosis. As approach, we utilize cell type-selective MMP14 gene targeting in mice to assess the effect on vascular wall tissue damage, inflammation and gene regulation. Through these studies, we are able to determine the role of MMP14 expressed by adipocytes and vascular smooth muscle cells in regulating atherogenesis. Expected outcomes will advance our understanding of the molecular mechanism underlying the disease link between obesity and CHD.

Public Health Relevance

Statement Obesity increases the risk of coronary heart disease (CHD). This research aims to determine the role of enzyme-mediated tissue remodeling in regulating the link between fat mass and atherosclerosis. Expected outcomes will help us develop a new approach to obesity and CHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL106332-02
Application #
8514054
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2012-07-20
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$185,045
Indirect Cost
$66,045
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Barnes 2nd, Richard H; Akama, Takeshi; Öhman, Miina K et al. (2017) Membrane-Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions. J Am Heart Assoc 6:
Tokunaga, Masakuni; Inoue, Mayumi; Jiang, Yibin et al. (2014) Fat depot-specific gene signature and ECM remodeling of Sca1(high) adipose-derived stem cells. Matrix Biol 36:28-38
Chun, Tae-Hwa; Inoue, Mayumi (2014) 3-D adipocyte differentiation and peri-adipocyte collagen turnover. Methods Enzymol 538:15-34
Moraes, Christopher; Labuz, Joseph M; Leung, Brendan M et al. (2013) On being the right size: scaling effects in designing a human-on-a-chip. Integr Biol (Camb) 5:1149-61
Inoue, Mayumi; Jiang, Yibin; Barnes 2nd, Richard H et al. (2013) Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice. Endocrinology 154:4548-59
Chun, Tae-Hwa (2012) Peri-adipocyte ECM remodeling in obesity and adipose tissue fibrosis. Adipocyte 1:89-95