Atherosclerotic coronary artery disease (CAD) remains a major cause of death and disability. New biological discoveries are required to transform our understanding of the disease and to spur clinical and therapeutic advances. Of CAD loci identified through recent genome wide association studies (GWAS), many have no apparent association with established risk factors or known mechanisms of atherosclerosis. Few new loci, however, have the combination of a clear candidate gene at the locus, plausible biology, and preliminary evidence that suggest specific translational hypotheses. Through GWAS, we discovered and replicated ADAMTS7 as a novel locus for coronary atherosclerosis. This finding has been reproduced in two other large-scale GWAS initiatives. ADAMTS7 has no relationship to traditional risk factors. This metalloproteinase, however, is expressed in human vascular smooth muscle cell (VSMC) and atherosclerotic lesions and our preliminary studies suggest that Adamts7-/- gene deletion in mice reduces the in vivo neointimal response to femoral artery injury. We hypothesize that ADAMTS7 promotes transition to VSMC synthetic phenotype and accelerates atherosclerosis by cleaving cartilage oligomeric matrix protein (COMP) an endogenous brake on VSMC migration, proliferation and matrix secretion. Here, we propose a series of experiments to:
(Aim 1) define ADAMTS7 structure-function for COMP and develop a high-throughput ADAMTS7 activity assay for use in mouse and human, (Aim 2) examine effects of germline loss-of-function (LOF) and gain-of-function (GOF) of Adamts7 on VSMC phenotype, vascular injury and atherosclerosis in mouse models, and (Aim 3) interrogate functional impact and CAD association of rare and low frequency non-synonymous ADAMTS7 alleles in human. Our investigative team is well positioned to execute these translational studies and advance our understanding of causation, directionality and mechanisms of ADAMTS7 action in atherosclerosis.

Public Health Relevance

Through GWAS, we have identified and validated ADAMTS7 as a novel gene for coronary atherosclerosis and heart disease. Little is known of ADAMTS7 function in the vasculature. In this proposal, we will define structure-function of ADAMTS7 interactions with target proteins, assess the effects of loss of function and gain of function on mouse atherosclerosis and VSMC function, and interrogate non-synonymous variants discovered upon sequencing of ADAMTS7 in humans for potential loss of function mutations that reduce risk of CAD. Our team is well positioned to advance understanding of ADAMTS7 mechanisms in atherosclerosis, thus establishing if this enzyme might be a valid therapeutic target for heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111694-02
Application #
8514059
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2012-07-19
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$593,459
Indirect Cost
$189,521
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Saleheen, Danish; Zhao, Wei; Young, Robin et al. (2017) Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation 135:2336-2353
Zhang, Hanrui; Reilly, Muredach P (2017) LIPA Variants in Genome-Wide Association Studies of Coronary Artery Diseases: Loss-of-Function or Gain-of-Function? Arterioscler Thromb Vasc Biol 37:1015-1017
Zhang, Hanrui; Reilly, Muredach P (2017) Human Induced Pluripotent Stem Cell-Derived Macrophages for Unraveling Human Macrophage Biology. Arterioscler Thromb Vasc Biol 37:2000-2006
Zhang, Hanrui; Hinkle, Christine C; O'Neill, Sean M et al. (2017) Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1. Obesity (Silver Spring) 25:1410-1420
Zhang, Hanrui; Shi, Jianting; Hachet, Melanie A et al. (2017) CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report. Arterioscler Thromb Vasc Biol 37:2156-2160
Ballantyne, Rachel L; Zhang, Xuan; Nuñez, Sara et al. (2016) Genome-wide interrogation reveals hundreds of long intergenic noncoding RNAs that associate with cardiometabolic traits. Hum Mol Genet 25:3125-3141
Golbus, Jessica R; Stitziel, Nathan O; Zhao, Wei et al. (2016) Common and Rare Genetic Variation in CCR2, CCR5, or CX3CR1 and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits. Circ Cardiovasc Genet 9:250-8
Ferguson, Jane F; Xue, Chenyi; Hu, Yu et al. (2016) Adipose tissue RNASeq reveals novel gene-nutrient interactions following n-3 PUFA supplementation and evoked inflammation in humans. J Nutr Biochem 30:126-32
Zhong, Ming; Zhang, Hanrui; Reilly, John P et al. (2015) ABO Blood Group as a Model for Platelet Glycan Modification in Arterial Thrombosis. Arterioscler Thromb Vasc Biol 35:1570-8
Bauer, Robert C; Tohyama, Junichiro; Cui, Jian et al. (2015) Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. Circulation 131:1202-1213

Showing the most recent 10 out of 26 publications