CD40 knockout combined with transverse aortic constriction synergistically augmented thrombin-induced platelet aggregation (49.1 vs 27.2) and blood clot contraction compared to wild-type mice.
Does CD40 knockout exacerbate pulmonary micro-thrombosis and oxidative stress in mice subjected to systolic pressure overload?
CD40 knockout exacerbates pulmonary micro-thrombosis and oxidative stress in a mouse model of heart failure induced by systolic pressure overload, highlighting a synergistic effect of inherent platelet defects and HF-induced endothelial activation.
cells), ∼1.7-fold more pulmonary fibrosis, and pulmonary vessel remodeling, as well as the consequent right ventricular hypertrophy. Mechanistically, our findings indicate that CD40 KO significantly enhanced TAC-induced pulmonary oxidative stress and pulmonary vascular endothelial cell activation, as indicated by upregulated vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 expression (ICAM-1). Moreover, CD40 KO and TAC synergistically augmented thrombin (49.1 ± 3.0 in CD40 KO TAC group vs 27.2 ± 4.8 in WT TAC group), collagen (51.4 ± 2.5 in CD40 KO TAC group vs 37.8 ± 2.4 in WT TAC group), and ADP-induced platelet aggregation (40.1 ± 2.1 in CD40 KO TAC group vs 31.0 ± 1.8 in WT TAC group) and blood clot contraction(0.92 ± 0.01 in CD40 KO TAC group vs 0.72 ± 0.03 in WT TAC group) in mice. Furthermore, mild but significant pulmonary micro-thrombosis and increased blood clot retraction (0.80 ± 0.02 in CD40 KO sham group vs 0.66 ± 0.02 in WT sham group) were also observed in CD40 KO mice under baseline (control) conditions. Collectively, these results demonstrate that the profound pulmonary micro-thrombosis observed in CD40 KO mice is the outcome of a synergistic effect involving an inherent platelet defect in CD40 KO mice, combined with HF-induced pulmonary endothelial oxidative stress, endothelial activation, and systemic platelet activation. This unique lung micro-thrombosis model may serve as a useful tool for investigating the mechanisms and therapeutic strategies for pulmonary micro-thrombosis, particularly under conditions of existing HF.
Yue et al. (Sat,) conducted a other in Systolic pressure overload and heart failure. CD40 knockout and transverse aortic constriction (TAC) vs. Wild-type mice with TAC, and sham-operated mice was evaluated on Pulmonary oxidative stress, vessel remodeling, microvascular thrombosis, and platelet aggregation. CD40 knockout combined with transverse aortic constriction synergistically augmented thrombin-induced platelet aggregation (49.1 vs 27.2) and blood clot contraction compared to wild-type mice.