Mark C Blaser1, Kuiru Wei1, Rachel L E Adams1, Yu-Qing Zhou1, Laura-Lee Caruso1, Zahra Mirzaei1, Alan Y-L Lam1, Richard K K Tam1, Hangjun Zhang1, Scott P Heximer1, R Mark Henkelman1, Craig A Simmons2. 1. 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, Hospital for Sick Children, Toronto, Ontario, Canada (Y.-Q.Z., R.M.H.). 2. 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, Hospital for Sick Children, Toronto, Ontario, Canada (Y.-Q.Z., R.M.H.). c.simmons@utoronto.ca.
Abstract
RATIONALE: 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. OBJECTIVE: The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease. METHODS AND RESULTS: In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein-coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used Npr2+/- and Npr2+/-;Ldlr-/- 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 Npr2+/- fibroblasts was insensitive to CNP treatment, whereas aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with bicuspid aortic valves than those with tricuspid valves. CONCLUSIONS: 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.
RATIONALE: 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. OBJECTIVE: The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease. METHODS AND RESULTS: In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein-coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used Npr2+/- and Npr2+/-;Ldlr-/- 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 Npr2+/- fibroblasts was insensitive to CNP treatment, whereas aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with bicuspid aortic valves than those with tricuspid valves. CONCLUSIONS: 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.
Authors: Petra Büttner; Lukas Feistner; Philipp Lurz; Holger Thiele; Joshua D Hutcheson; Florian Schlotter Journal: Front Cardiovasc Med Date: 2021-05-10
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Authors: Dewy C van der Valk; Casper F T van der Ven; Mark C Blaser; Joshua M Grolman; Pin-Jou Wu; Owen S Fenton; Lang H Lee; Mark W Tibbitt; Jason L Andresen; Jennifer R Wen; Anna H Ha; Fabrizio Buffolo; Alain van Mil; Carlijn V C Bouten; Simon C Body; David J Mooney; Joost P G Sluijter; Masanori Aikawa; Jesper Hjortnaes; Robert Langer; Elena Aikawa Journal: Nanomaterials (Basel) Date: 2018-05-03 Impact factor: 5.076