Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice
Rationale: Aortic valve disease is a cell-mediated process without effective pharmacotherapy. C-type natriuretic peptide (CNP) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells (VICs), and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo.
Objective: To determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease.
Methods and Results: In cultured porcine VICs, CNP inhibited pathological differentiation via the guanylate cyclase natriuretic peptide receptor 2 (NPR2) and not the G-protein-coupled clearance receptor NPR3. 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, while aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice vs. 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 (BAVs), with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cyclic guanosine monophosphate-dependent protein kinase (cGK) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 in cultured porcine VICs. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with BAVs 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.
- natriuretic peptide receptor 2
- C-type natriuretic peptide
- bicuspid aortic valve
- aortic valve stenosis
- Received May 3, 2017.
- Revision received December 20, 2017.
- Accepted December 21, 2017.