Restenosis remains the most significant clinical challenge limiting the success of angioplasty and/or stenting. Neointimal hyperplasia is the primary reason for in-stent restenosis. The objective of this proposal is to use variations among mouse strains in injury-induced neointimal hyperplasia to identify genetic factors that contribute to the development of post-angioplasty/stent restenosis. On the apolipoprotein E-deficient (apoE-/-) background, inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) differ markedly in injury-induced neointimal hyperplasia. B6.apoE-/- mice readily develop neointimal hyperplasia whereas CSH.apoE-/- mice are totally resistant to lesion formation despite the fact that the two strains have comparable hyperlipidemia on a chow diet. The F1 hybrids are intermediate in the phenotype, indicating a codominant control of the phenotype in the mice. Immediately following arterial injury is deposition of a layer of platelets at sites of vascular injury. Subsequently, leukocyte recruitment and infiltration occur. Recruited macrophages and lymphocytes and damaged endothelial cells and vascular smooth muscle cells (SMC) release cytokines, growth factors, and matrix metalloproteinases (MMP) that stimulate SMC in the medial wall to proliferate and migrate into the damaged intima. We hypothesize that genetic factors that influence the induction of cytokines and growth factors or that modulate the proliferation of vascular smooth muscle cells contribute to the variation in neointimal hyperplasia of the two strains. To test this hypothesis, B6.apoE-/- mice will be mated with CSH.apoE-/- mice to generate F1 mice, which will be subsequently intercrossed to generate a cohort of F2 mice. The male F2 mice, together with male F1 and two parental strains, will be subject to endothelial denudation of the left common carotid artery. Neointimal thickening will be quantitated by light microscopy. Blood will be collected for assessment of fasting lipid and inflammatory marker levels. Genome-wide scans will be performed using microsatellite markers to define the genetic loci that are linked to differences in the phenotypes between B6 and C3H strains. After the genome screen has detected chromosomal regions that show linkage with neointimal lesions, we will type additional closely spaced polymorphic markers to narrow the regions. One to two major QTLs for neointimal hyperplasia will be dissected through construction and analysis of congenic strains. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL082881-01A2
Application #
7264208
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Srinivas, Pothur R
Project Start
2007-06-06
Project End
2010-05-31
Budget Start
2007-06-06
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$265,125
Indirect Cost
Name
University of Virginia
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Rowlan, Jessica S; Zhang, Zhimin; Wang, Qian et al. (2013) New quantitative trait loci for carotid atherosclerosis identified in an intercross derived from apolipoprotein E-deficient mouse strains. Physiol Genomics 45:332-42
Rowlan, Jessica S; Li, Qiongzhen; Manichaikul, Ani et al. (2013) Atherosclerosis susceptibility Loci identified in an extremely atherosclerosis-resistant mouse strain. J Am Heart Assoc 2:e000260
Zhang, Zhimin; Rowlan, Jessica S; Wang, Qian et al. (2012) Genetic analysis of atherosclerosis and glucose homeostasis in an intercross between C57BL/6 and BALB/cJ apolipoprotein E-deficient mice. Circ Cardiovasc Genet 5:190-201
Li, Jing; Lu, Zongji; Wang, Qian et al. (2012) Characterization of Bglu3, a mouse fasting glucose locus, and identification of Apcs as an underlying candidate gene. Physiol Genomics 44:345-51
Lu, Zongji; Yuan, Zuobiao; Miyoshi, Toru et al. (2011) Identification of Soat1 as a quantitative trait locus gene on mouse chromosome 1 contributing to hyperlipidemia. PLoS One 6:e25344
Manichaikul, Ani; Wang, Qian; Shi, Yu Lena et al. (2011) Characterization of Ath29, a major mouse atherosclerosis susceptibility locus, and identification of Rcn2 as a novel regulator of cytokine expression. Am J Physiol Heart Circ Physiol 301:H1056-61
Li, Jing; Wang, Qian; Chai, Weidong et al. (2011) Hyperglycemia in apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility. Cardiovasc Diabetol 10:117
Shi, Weibin; Zhang, Zhimin; Chen, Mei-Hua et al. (2010) Genes within the MHC region have a dramatic influence on radiation-enhanced atherosclerosis in mice. Circ Cardiovasc Genet 3:409-13
Yuan, Zuobiao; Pei, Hong; Roberts, Drew J et al. (2009) Quantitative trait locus analysis of neointimal formation in an intercross between C57BL/6 and C3H/HeJ apolipoprotein E-deficient mice. Circ Cardiovasc Genet 2:220-8
Yuan, Zuobiao; Su, Zhiguang; Miyoshi, Toru et al. (2008) Quantitative trait locus analysis of circulating adhesion molecules in hyperlipidemic apolipoprotein E-deficient mice. Mol Genet Genomics 280:375-83