Tuesday, May 7, 2024
5/7/2024
Project Summary Vascular calcification is a hallmark of atherosclerotic cardiovascular diseases such as myocardial infarction and stroke, which are the leading causes of morbidity and mortality in the world. Although coronary artery calcification (CAC) is a strong independent risk factor for cardiovascular disease, the genetic determinants of CAC and the molecular mechanisms of vascular calcification remain incompletely elucidated. In a multi-cohort study with more than 22,000 participants, we identified single nucleotide polymorphisms in the arylsulfatase E (ARSE) locus that are associated with coronary artery calcification. In an in vitro model of calcification, our preliminary experiments demonstrated that inhibition of ARSE or a related protein sulfatase 1 (SULF1) prevented the calcification of coronary and aortic vascular smooth muscle cells (VSMCs). Furthermore, we found that SULF1-deficient mice are protected from developing vascular calcification. Based on our preliminary evidence, combining a human genome-wide association study, in vitro VSMC experiments, and an in vivo murine model of vascular calcification, we have identified ARSE and SULF1 to be novel activators of vascular calcification. The overall objective of this proposal is to understand the molecular mechanisms by which these sulfatases promote vascular calcification and atherosclerosis. First, using a series of VSMC functional assays, we propose to determine the specific role of ARSE and SULF1 in promoting VSMC osteogenic phenotype switch and calcification. We will also ascertain whether the sulfatases induce the development of vascular calcification and atherosclerosis in vivo using mouse models. Second, we have uncovered an important role for ARSE and SULF1 in regulating autophagy and bone morphogenetic protein (BMP) signaling. We will determine if the effects of ARSE and SULF1 on VSMC-mediated vascular calcification is dependent on their effects on autophagy and/or BMP signaling. Lastly, we will examine the associations of the ARSE index variant with a range of electronic health record phenotypes, as well as with additional vascular calcification phenotypes including aortic calcium volume and density, aortic valve calcification and mitral annular calcification. Furthermore, we will conduct the first genome-wide association study to identify novel genetic determinants of coronary calcification density. The experiments proposed will provide important mechanistic insights into the function of sulfatases in the vasculature and into the underlying molecular and genetic mechanisms of vascular calcification and atherosclerosis.
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