OBJECTIVE: Cardiovascular disease (CVD) is a com mon comorbidity and a major cause of death in patients with chronic obstructive pulmonary disease (COPD). Pulmonary microvascular barrier dysfunction is in-volved in the development of chronic inflammation in COPD and induces systemic inflammation. Tongxinluo (TXL) improves the function of vascular endothelial cells. However, the effect of TXL on pulmonary micro- vascular barrier function remains unknown. This study aims to explore the molecular mechanism of pulmonary microvascular barrier dysfunction in COPD combined with atherosclerosis and the related targets of TXL in this dysfunction. STUDY DESIGN: In vivo, the COPD with atheroscle rosis mouse model on the ApoE(-/-) background was established by cigarette smoke combined with a high-fat diet. The animals were administered TXL, atorvastatin (Ato), and TXL+Ato once a day for 20 weeks. Then, the biomarkers of the Rac1/Cdc42 pathway were measured. In vitro, human pulmonary microvascular endothelial cells (HPMECs) were pretreated with TXL and incubated with cigarette smoke extract (CSE) to establish the model. The permeability of the endothelial monolayer and tight junction protein expression were determined. RESULTS: The Rac1/Cdc42 signaling pathway participated in the deterioration of the pulmonary microvascular barrier, and treatment with TXL decreased the levels of Rac1, Cdc42, and p-Rac1 + Cdc42. Then, knocking down the expression of Rac1 in HPMECs using small-interfering RNA decreased the protein levels of Rac1, Cdc42, and p-Rac1 +Cdc42 while increasing the ability of HPMECs to maintain the pulmonary micro- vascular barrier function, and TXL had a synergistic effect on the inhibition of the Rac1/Cdc42 signaling pathway with siRNA. CONCLUSION: The Rac1/Cdc42 pathway is involved in pulmonary microvascular barrier dysfunction, and TXL can protect pulmonary microvascular barrier function by inhibiting the expression of Rac1/Cdc42 signaling pathway-related proteins in HPMECs.