{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:53:28Z","timestamp":1793408008031,"version":"4.5.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2018,2,2]]},"abstract":"\n \n Rationale:<\/jats:underline>\n <\/jats:title>\n Aortic valve disease is a cell-mediated process without effective pharmacotherapy. CNP (C-type natriuretic peptide) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo.<\/jats:p>\n <\/jats:sec>\n \n \n Objective:<\/jats:underline>\n <\/jats:title>\n The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease.<\/jats:p>\n <\/jats:sec>\n \n \n Methods and Results:<\/jats:underline>\n <\/jats:title>\n \n In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein\u2013coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used\n Npr2<\/jats:italic>\n +\/\u2212<\/jats:sup>\n and\n Npr2<\/jats:italic>\n +\/<\/jats:sup>\n \u2212<\/jats:sup>\n ;\n Ldlr<\/jats:italic>\n \u2212\/<\/jats:sup>\n \u2212<\/jats:sup>\n mice and wild-type littermate controls to examine the valvular effects of deficient CNP\/NPR2 signaling in vivo, in the context of both moderate and advanced aortic valve disease. Myofibrogenesis in cultured\n Npr2<\/jats:italic>\n +\/<\/jats:sup>\n \u2212<\/jats:sup>\n fibroblasts was insensitive to CNP treatment, whereas aged\n Npr2<\/jats:italic>\n +\/<\/jats:sup>\n \u2212<\/jats:sup>\n and\n Npr2<\/jats:italic>\n +\/<\/jats:sup>\n \u2212<\/jats:sup>\n ;\n Ldlr<\/jats:italic>\n \u2212\/\u2212 mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in\n Npr2<\/jats:italic>\n +\/<\/jats:sup>\n \u2212<\/jats:sup>\n and\n Npr2<\/jats:italic>\n +\/<\/jats:sup>\n \u2212<\/jats:sup>\n ;\n Ldlr<\/jats:italic>\n \u2212\/<\/jats:sup>\n \u2212<\/jats:sup>\n mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for\n Npr2<\/jats:italic>\n had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those\n Npr2<\/jats:italic>\n +\/\u2212<\/jats:sup>\n with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in\n Npr2<\/jats:italic>\n +\/\u2212<\/jats:sup>\n valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged\n Npr2<\/jats:italic>\n +\/\u2212<\/jats:sup>\n ;\n Ldlr<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice developed dilatation of the ascending aortic, with greater aneurysmal progression in\n Npr2<\/jats:italic>\n +\/\u2212<\/jats:sup>\n mice with bicuspid aortic valves than those with tricuspid valves.\n <\/jats:p>\n <\/jats:sec>\n \n \n Conclusions:<\/jats:underline>\n <\/jats:title>\n Our data establish CNP\/NPR2 signaling as a novel regulator of aortic valve development and disease and elucidate the therapeutic potential of targeting this pathway to arrest disease progression.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.117.311194","type":"journal-article","created":{"date-parts":[[2017,12,22]],"date-time":"2017-12-22T10:15:42Z","timestamp":1513937742000},"page":"405-416","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":57,"title":["Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice"],"prefix":"10.1161","volume":"122","author":[{"given":"Mark C.","family":"Blaser","sequence":"first","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuiru","family":"Wei","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.E.","family":"Adams","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Qing","family":"Zhou","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura-lee","family":"Caruso","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Mirzaei","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan Y.-L.","family":"Lam","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K.K.","family":"Tam","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott P.","family":"Heximer","sequence":"additional","affiliation":[{"name":"From the Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada (M.C.B., R.L.E.A., Y.-Q.Z., L.-l.C., Z.M., A.Y.-L.L., R.K.K.T., H.Z., S.P.H., C.A.S.); Institute of Biomaterials and Biomedical Engineering (M.C.B., K.W., R.L.E.A., A.Y.-L.L., R.K.K.T., C.A.S.), Department of Physiology (H.Z., S.P.H.), and Department of Mechanical and Industrial Engineering (L.-l.C., Z.M., C.A.S.), University of Toronto, Ontario, Canada; and Mouse Imaging Centre,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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