Abstract
Closure of the ductus arteriosus (DA) involves vasoconstriction and vascular remodeling. Cinaciguat, a soluble guanylyl cyclase (sGC) activator, was reported with vasodilatory and anti-remodeling effects on pulmonary hypertensive vessels. However, its effects on DA are not understood. Therefore, we investigated whether cinaciguat regulated DA patency and examined its underlying mechanisms. In vivo, we found that cinaciguat (10 mg/kg, i.p. at birth) prevented DA closure at 2 h after birth with luminal patency and attenuated intimal thickening. These anti-remodeling effects were associated with enhanced expression of cyclic guanosine monophosphate (cGMP) in DA. Ex vivo, cinaciguat dilated oxygen-induced DA constriction dose-dependently. Such vasodilatory effect was blunted by KT-5823, a PKG inhibitor. In DA smooth muscle cells (DASMCs), we further showed that cinaciguat inhibited angiotensin II (Ang II)-induced proliferation and migration of DASMCs. In addition, cinaciguat inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production. Finally, Ang II-activated MAPKs and Akt were also inhibited by cinaciguat. In conclusion, cinaciguat prevents postnatal DA closure by vasodilation and anti-remodeling through the cGMP/PKG pathway. The mechanisms underlying anti-remodeling effects include anti-proliferation and anti-migration, with attenuation of mitochondrial ROS production, MAPKs, and Akt signaling. Thus, this study implicates that sGC activation may be a promising novel strategy to regulate DA patency.
Highlights
Ductus arteriosus (DA) is a vital vessel connecting the pulmonary arteries and aorta during fetal period and mostly will be closed soon after birth
We explored the molecular mechanisms underlying these effects on ductus arteriosus (DA) smooth muscle cells (DASMCs) treated with angiotensin II (Ang II), a mediator implicated in DA closure (Crockett et al, 2019; Hamrick et al, 2020)
We found that cinaciguat attenuated Ang II-induced DNA synthesis of DASMCs dosedependently (Figure 5B)
Summary
Ductus arteriosus (DA) is a vital vessel connecting the pulmonary arteries and aorta during fetal period and mostly will be closed soon after birth. For treating newborns with ductus-dependent congenital heart defects (CHDs), PGE1 is the only choice to keep the DA patent for maintaining pulmonary circulation. Both PG synthetase inhibitors and PGE1 have several significant adverse events (Lewis et al, 1981; Oncel and Erdeve, 2015). Developing a novel pharmacological target is essential for newborns with PDAs and ductus-dependent CHDs. Cinaciguat, a soluble guanylyl cyclase (sGC) activator, could activate heme-deficient sGC to increase intracellular cyclic guanosine monophosphate (cGMP) for further biological effects and is currently used in patients with pulmonary hypertension (Evgenov et al, 2006). We explored the molecular mechanisms underlying these effects on DA smooth muscle cells (DASMCs) treated with angiotensin II (Ang II), a mediator implicated in DA closure (Crockett et al, 2019; Hamrick et al, 2020)
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