MATRIX METALLOPROTEINASE CLEAVAGE OF VERSICAN IN CARDIAC OUTLET REMODELING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of the cardiac outflow tract (OFT), i. e. aorta, pulmonary artery and semi-lunar valves, is a poorly understood process yet OFT malformations constitute 30% of all congenital heart defects. The process by which the proteoglycan-rich extracellular matrix (ECM) of the common OFT is remodeled during development to form the fibrous and elastic connective tissues of the adult heart has only recently begun to be investigated and is the focus of my COBRE research. Previous studies have shown that the proteoglycan versican is essential for cardiac development and is prominently expressed in the developing cardiac outlet. Furthermore the cleavage of versican by the ADAMTS (A Disintegrin and Metalloproteinase with ThromboSpondin motifs) family of ECM proteinases occurs in key steps of cardiac outlet formation. Therefore this suggests that ADAMTS proteinases may be critical for remodeling of the proteoglycan rich matrix into the fibrous ECM of the mature arterial wall and valves. Importantly, anomalies of the cardiovascular ECM also lead to relatively common clinical manifestations such as aortic rupture and myxomatous valve disease. A hallmark of cardiovascular disease progression is the re-expression of developmental programs including an ECM rich in versican. Taken together with the fact that ADAMTS proteinases maintain expression within the adult heart, investigation into the role of ADAMTS proteinases should contribute to our understanding of both development and homeostasis of the cardiovascular ECM.