Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE

Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.

Aortic Aneurysm/*genetics ; Aortic Valve/*abnormalities ; Heart Valve Diseases/*genetics ; Natriuretic Peptide, C-Type/*physiology ; Receptors, Atrial Natriuretic Factor/*deficiency ; Ventricular Dysfunction, Left/*genetics; Animals ; Aorta/pathology ; Aortic Aneurysm/physiopathology ; Aortic Valve/physiopathology ; Aortic Valve Stenosis/genetics ; Aortic Valve Stenosis/physiopathology ; Bicuspid Aortic Valve Disease ; Calcinosis/genetics ; Calcinosis/physiopathology ; Cells, Cultured ; Collagen/biosynthesis ; Cyclic GMP/physiology ; Cyclic GMP-Dependent Protein Kinase Type I/metabolism ; Extracellular Matrix/pathology ; Hyperlipidemias/complications ; Hyperlipidemias/genetics ; Mice ; Mice, Knockout ; Myofibroblasts/cytology ; Natriuretic Peptide, C-Type/pharmacology ; Osteogenesis ; Proteoglycans/biosynthesis ; Receptors, Atrial Natriuretic Factor/physiology ; Receptors, LDL/deficiency ; Receptors, LDL/genetics ; Swine ; Ventricular Dysfunction, Left/physiopathology

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.
(© 2017 American Heart Association, Inc.)

MOP-102721 Canada CIHR

Keywords: aortic aneurysm; aortic valve; aortic valve stenosis; natriuretic peptide, C-type; ventricular dysfunction, left

0 (Proteoglycans)
0 (Receptors, LDL)
127869-51-6 (Natriuretic Peptide, C-Type)
9007-34-5 (Collagen)
EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I)
EC 4.6.1.2 (Receptors, Atrial Natriuretic Factor)
EC 4.6.1.2 (atrial natriuretic factor receptor B)
H2D2X058MU (Cyclic GMP)

Date Created: 20171224 Date Completed: 20190703 Latest Revision: 20201218

20221213

10.1161/CIRCRESAHA.117.311194

29273600