Calcific aortic valve disease: novel insights into nitric oxide signalling

The endothelium covering the disease-prone fibrosa is exposed to LDL-like particles [e.g. Lp(a)] and low-magnitude oscillatory shear stress, that can perturb endothelial nitric oxide signalling. Indeed, diminished BH4 levels lead to eNOS uncoupling, and increased ONOO– formation, thus inducing DNA damage and DRP1 nitration, which culminates in the myofibro-/osteoblastic activation of VICs and hence accelerated CAVD progression. Conversely, high eNOS-mediated NO biosynthesis is considered to protect from fibro-calcific remodelling largely by fuelling pathways that maintain VIC quiescence, e.g. via NOTCH1 or guanylate cyclase activation. Folic acid protects from hypercholesterolaemia-induced CAVD by boosting endothelial BH4 bioavailability through enhanced DHFR expression. Protective pathways regulated by NO are shown in green, and deleterious pathways in red. ALPL, alkaline phosphatase; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; CAVD, calcific aortic valve disease; DHFR, dihydrofolate reductase; eNOS, endothelial nitric oxide synthase; GCH1, GTP cyclohydrolase I; GC, guanylyl cyclase; HEY1, hairy/enhancer-of-split related with YRPW motif protein 1; RUNX2, RUNX family transcription factor 2; VEC valvular endothelial cell; and VIC valvular interstitial cell. Adapted from Kraler et al.1