Contribution of Nlrp3 inflammasomes to PDGF‐BB‐induced inflammation and pyroptosis in arterial smooth muscle cells and atherogenesis

Recent studies have demonstrated a critical role of Nlrp3 inflammasome and its products in regulating vascular smooth muscle cell (SMC) homeostasis in atherogenesis. However, it remains elusive whether or not smooth muscle Nlrp3 inflammasome activation is directly involved in regulating SMC function and vascular remodeling. Using primary cultured SMCs isolated from mouse arteries, we demonstrated that PDGF‐BB stimulation significantly upregulated the Nlrp3 expression and increased caspase‐1 activation in SMCs. PDGF‐BB induced inflammatory responses in SMCs as shown by increased expression of VCAM‐1 and ICAM‐1 and enhanced adhesion of monocytes by SMC monolayers, and these effects were suppressed by a caspase‐1 inhibitor Ac‐YVAD. Furthermore, PDGF‐BB significantly induced pyroptosis in SMCs as evidenced by increased caspase‐1‐dependent cell death and activation of GSDMD (membrane pore forming protein), caspase‐11, and caspase‐3. Conversely, PDGF‐BB‐induced SMC proliferation and migration was not affected by Nlrp3 inflammasome inhibitor Ac‐YVAD. Using a partial carotid artery ligation atherogenesis model in mice with PCSK9 overexpression and fed high fat/cholesterol Paigen diet (PD), we demonstrated that hypercholesterolemia by PCSK9/PD treatment markedly increased activation of caspase‐1 and upregulated expression of IL‐1β, VCAM‐1, and ICAM‐1 in the arterial wall of partial ligated carotid arteries, which was accompanied by elevated inflammatory cell infiltration and neointimal formation when compared to normal diet treated controls. Importantly, these hypercholesterolemia‐induced changes were either not observed or markedly attenuated in the carotid arterial wall of Nlrp3‐null mice. Together, our data demonstrate that activation of smooth muscle Nlrp3 inflammasomes can directly lead to caspase‐1‐dependent inflammation and pyroptosis in SMCs, which may, at least, partially contribute to hypercholesterolemia‐induced disturbance in arterial smooth muscle homeostasis and vascular remodeling.