ADAMTS7 Cleavage and Vascular Smooth Muscle Cell Migration Is Affected by a Coronary-Artery-Disease-Associated Variant

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• 作者：Xiangyuan Pu¹ ; ² ; ⁶ ; Qingzhong Xiao¹ ; ⁶ ; Stefan Kiechl³ ; Kenneth Chan¹ ; Fu Liang Ng¹ ; Shivani Gor¹ ; Robin N. Poston¹ ; Changcun Fang¹ ; Ashish Patel¹ ; Ece C. Senver¹ ; Sue Shaw-Hawkins¹ ; Johann Willeit³ ; Chuanju Liu⁴ ; Jianhua Zhu² ; Arthur T. Tucker¹ ; Qingbo Xu⁵ ; Mark J. Caulfield¹ ; Shu Ye¹ ; ^{s.ye@qmul.ac.uk}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：7 March, 2013
• 年：2013
• 卷：92
• 期：3
• 页码：366-374
• 全文大小：1124 K

文摘

Recent genome-wide association studies have revealed an association between variation at the ADAMTS7 locus and susceptibility to coronary artery disease (CAD). Furthermore, in a population-based study cohort, we observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a Ser-to-Pro substitution in the prodomain of the protease ADAMTS7. In light of these data, we sought a mechanistic explanation for this association. We found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) of the G/G genotype for rs3825807 had reduced migratory ability, and conditioned media of VSMCs of the G/G genotype contained less of the cleaved form of thrombospondin-5, an ADAMTS7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration. Furthermore, we found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by VSMCs of the G/G genotype and that the Ser-to-Pro substitution affected ADAMTS7 prodomain cleavage. The results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD rendering a reduction in ADAMTS7 function.