Calcific aortic valve disease (CAVD) is a prevalent age-related valvulopathy characterized by high morbidity and mortality. CAVD pathogenesis involves maladaptive differentiation of valvular interstitial cells (VICs) into profibrotic and osteogenic phenotypes, yet the underlying mechanisms remain unclear. Emerging evidence implicates cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling in mitigating calcification. However, its molecular actions are poorly defined. Here, we found that the cGMP-PKG signaling pathway is suppressed in calcified aortic valves and that serum cGMP levels inversely correlate with calcification severity and transvalvular pressure gradients in patients with CAVD. In viv... More
Calcific aortic valve disease (CAVD) is a prevalent age-related valvulopathy characterized by high morbidity and mortality. CAVD pathogenesis involves maladaptive differentiation of valvular interstitial cells (VICs) into profibrotic and osteogenic phenotypes, yet the underlying mechanisms remain unclear. Emerging evidence implicates cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling in mitigating calcification. However, its molecular actions are poorly defined. Here, we found that the cGMP-PKG signaling pathway is suppressed in calcified aortic valves and that serum cGMP levels inversely correlate with calcification severity and transvalvular pressure gradients in patients with CAVD. In vivo, protein kinase G type I (PKGI) haploinsufficiency aggravated aortic valve calcification and the hemodynamic burden in a CAVD mouse model. In vitro, PKGI silencing promoted osteogenic differentiation of human VICs, whereas pharmacological activation of cGMP-PKG signaling by vericiguat, BNP, or sildenafil attenuated calcium deposition, with vericiguat showing the strongest effect. Vericiguat also reduced leaflet calcification ex vivo and alleviated disease progression in two in vivo CAVD models. Mechanistically, PKGI enhances autophagic flux by phosphorylating ULK1 at Ser556, preserving mitochondrial function, and reducing oxidative stress. Together, our work indicates that the cGMP-PKG pathway protects against aortic valve calcification by promoting ULK1-mediated autophagy, highlighting vericiguat as a potential therapy for CAVD.
