Continuous administration of CNP-53 prevented the development of pulmonary hypertension in mouse models via endothelial GC-B signaling and ameliorated severe PAH in rodent models.
Does C-type natriuretic peptide (CNP) administration prevent or improve pulmonary arterial hypertension in preclinical models?
Endothelial CNP/GC-B signaling exerts pivotal preventative and therapeutic effects against the development of pulmonary hypertension in preclinical models, highlighting CNP as a potential therapeutic target for PAH.
Abstract C-type natriuretic peptide (CNP) is released from endothelial cells and acts as an autocrine/paracrine mediator, regulating systemic blood pressure and vascular remodeling via guanylyl cyclase-B (GC-B) and natriuretic peptide receptor-C. We investigate the impact of vascular CNP/GC-B signaling on the development of pulmonary arterial hypertension (PAH). Mice developing pulmonary hypertension (PH) show reduced pulmonary NPPC and NPR2 expression than mice without PH. S imilarly, endothelial cells (EC) from patients with idiopathic PAH exhibit lower NPPC and NPR2 expression than control EC. EC-specific CNP or GC-B conditional knockout (CNP ecKO or GC-B ecKO) mice, but not smooth muscle cell-specific GC-B conditional knockout (GC-B smcKO) mice, show more severe PH and greater expression of Edn1, Il6, Ccl2 and Tgfb1 mRNAs than their genetic controls in PAH models. CNP suppresses hypoxia-induced increases in expression of these mRNAs and restored SMAD2/3-SMAD1/5/9 balance in cultured human pulmonary arterial EC. Moreover, CNP administration prevents PH in genetic control and GC-B-smcKO mice but not in GC-B ecKO mice. CNP administration also has therapeutic effects against Sugen5416-hypoxia PAH models as well as additive benefits with established therapies. Endothelial CNP/GC-B signaling thus exerts pivotal preventative effects against development of PH, suggesting the therapeutic potential of CNP for PAH.
Yanagisawa et al. (Tue,) conducted a other in Pulmonary arterial hypertension. CNP-53 vs. Vehicle was evaluated on Right ventricular systolic pressure (RVSP) and right ventricle weight/left ventricle plus interventricular septum weight [RV/(LV + IVS)] ratio. Continuous administration of CNP-53 prevented the development of pulmonary hypertension in mouse models via endothelial GC-B signaling and ameliorated severe PAH in rodent models.