GDF11 Alleviates Vascular Calcification in VitD3-Overloaded Mice Through Inhibition of Inflammatory NF-κB Signal

Abstract

Vascular calcification, an age-associated disorder, is a highly regulated biological process similar to bone formation. Growth differentiation factor 11 (GDF11), a secreted member of the transforming growth factor beta (TGF-β) superfamily, has been shown to act as an anti-aging factor in the brain, heart, skin, and skeletal muscle. Nevertheless, whether GDF11 affects vascular calcification and the underlying mechanisms remain unclear. In the present study, beta-glycerophosphate and calcium chloride-induced calcification of vascular smooth muscle cells (VSMCs) and a VitD₃-overloaded mouse model were used to investigate the role of GDF11 in vascular calcification. Our results revealed that the knockdown of GDF11 by siRNA promoted the calcification of rat VSMCs, whereas GDF11 treatment significantly reduced the calcification of human and rat VSMCs in vitro, as detected by alizarin red staining and calcium content assay. Similarly, GDF11 treatment reduced the expression of bone-related molecules including Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2 (BMP2). Furthermore, ex vivo and in vivo studies confirmed the inhibitory effect of GDF11 on vascular calcification. Mechanistically, GDF11 treatment reduced the levels of NF-κB signaling molecules including NLRP3, phosphorylated p65, IL-6, and IL-1β in VSMCs. Additionally, GDF11 siRNA-induced VSMC calcification was repressed by NF-κB inhibitor PDTC treatment. Taken together, these findings suggest that GDF11 alleviates vascular calcification through inhibiting the NF-κB signal. Modulation of GDF11 may represent a therapeutic strategy for vascular calcification.