Abstract 14337: Deficiency of C-type Natriuretic Peptide Signaling Promotes Aortic Stenosis in Mice
Background: Expression of C-type natriuretic peptide (CNP) is elevated in disease-protected regions of the normal aortic valve and reduced in stenotic valves. In vitro, CNP inhibits pathological myofibro- and osteoblastic differentiation of valvular interstitial cells, yet the functional impact of CNP on valvular homeostasis in vivo is unknown. We examined whether a deficiency in CNP signaling would result in accelerated progression of valvular heart disease in mice.
Methods: Homozygous knockout of CNP or its receptor Npr2 cause high levels of neonatal mortality (>75%), so male mice (background strain: C57BL/6J) haploinsufficient for Npr2 (Npr2+/-) and wild-type littermates (WT) were fed either a high-fat (HF, TD.88137) or control diet for 4 or 8 months (n = 9-15 per group). Blood pressure was measured via carotid artery catheterization, while aortic valve and cardiac function was assessed by high-resolution echo (30 MHz).
Results: Npr2+/- mice fed the HF diet for 8 months displayed small reductions vs. all other groups in systolic (114.2 ± 3.3 vs. 100.0 ± 4.0 mmHg, p < 0.01) and diastolic blood pressure (76.6 ± 2.2 vs. 65.8 ± 1.8 mmHg, p < 0.01), but there was no effect of diet on echocardiographic measurements. At 4 months, Npr2+/- mice developed impaired aortic valve function with elevated maximum transvalvular velocity (166.1 ± 12.2 cm/s vs. 126.6 ± 1.9 cm/s, p < 0.01) and reduced aortic valve opening area (AVA, 0.44 ± 0.03 vs. 0.67 ± 0.02 mm2, p < 0.001). Reductions in Npr2+/- AVA were maintained at 4 and 8 months (34.2% and 32.2% respectively). While transvalvular velocity in 8 month Npr2+/- mice remained elevated compared to WTs (139.2 ± 7.2 vs. 120.0 ± 2.0 cm/s, p < 0.05), this increase was blunted vs. that of the 4 month Npr2+/- mice (p < 0.05). Blunting was caused by impaired LV systolic function: LVOT velocity of 8 month Npr2+/- mice was reduced by 18.5% vs. all other groups (p < 0.001), as were LV ejection fraction (by 22.3%, p < 0.001) and fractional shortening (27.2%, p < 0.001).
Conclusions: Impairment of CNP signaling leads to valvular and LV dysfunction in mice, thereby evoking a phenotype of low-flow, low-ejection fraction stenosis. These findings are the first to establish a functional role for CNP in the aortic valve and suggest avenues for novel therapeutic intervention.
- © 2013 by American Heart Association, Inc.