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Cardiovascular comorbidities are pervasive in chronic obstructive pulmonary disease (COPD) and often result in serious adverse cardiovascular events. Tongxinluo (TXL) has been clinically verified to treat atherosclerosis (AS), improve lung function and alleviate dyspnoea. The present study aimed to explore the effect of lung microvascular barrier dysfunction on AS in COPD and the potential pulmonary protective mechanisms of TXL in COPD complicated with AS. COPD complicated with AS was induced in mice by cigarette smoke (CS) exposure and high-fat diet (HFD) feeding. The mice were treated with atorvastatin (ATO), TXL or combination therapy (ATO+TXL) for 20 weeks. Pulmonary function, lung pathology, serum lipid levels, atherosclerotic plaque area and indicators of barrier function, oxidative stress and ferroptosis in lung tissue were evaluated. In vitro, human pulmonary microvascular endothelial cells (HPMECs) were pretreated with TXL for 4 h and then incubated with cigarette smoke extract (CSE) and homocysteine (Hcy) for 36 h to induce barrier dysfunction. Then the indicators of barrier function, oxidative stress and ferroptosis were measured. The results demonstrate that CS aggravated dyslipidaemia, atherosclerotic plaque formation, pulmonary function decline, pathological injury, barrier dysfunction, oxidative stress and ferroptosis in the HFD-fed mice. However, these abnormalities were partially reversed by ATO and TXL. Similar results were observed in vitro. In conclusion, pulmonary microvascular barrier dysfunction plays an important role by which COPD affects the progression of AS, and ferroptosis may be involved. Moreover, TXL delays the progression of AS and reduces cardiovascular events by protecting the pulmonary microvascular barrier and inhibiting ferroptosis.

Background Chinese traditional medicine Tongxinluo capsule (TXL) has been widely used for cardiovascular diseases. Both clinical and basic studies showed that TXL had effective effects on atherosclerosis. However, the mechanism researches were relatively scattered. This study was aimed to fully evaluate the potential mechanisms of TXL on atherosclerosis as a whole. Method One hundred apoE-/- mice (male, 12 weeks old) were randomly divided into five groups (n = 20 each group) Mice in the control group were fed normal diet and mice in the other four groups (intervention groups) were fed high fat diet. The intervention groups were randomly divided into normal saline (NS) group and TXL treatment groups, and the latter were further divided into three subgroups: low-dose TXL (TXL-L), medium-dose TXL (TXL-M) and high-dose TXL (TXL-H), with TXL dosage at 0.38, 0.75, 1.5 g/kg/d by gavage, respectively. After sixteen weeks of intervention, all mice underwent euthanasia. Gene expression profiles with aortic tissues were determined by genechip. A Gene Ontology (GO) analysis was performed to interpret the functional implications of altered genes. Result Histological and morphological analysis demonstrated that TXL at different doses all reduced plaque burden and plaque size. The expressions of IL-6, TNF-ɑ and MMP-2 were significantly decreased in the TXL intervention groups compared with control. In atherosclerotic lesions of TXL groups 3284 genes altered compared with control, and 632 genes changed in the TXL-H group compared with the NS group. Of these genes, 48 showed a decrease which were high in atherosclerosis, and 56 showed a increase which were low in atherosclerosis after TXL intervention. Significantly altered genes were found to be involved in the aspects of hormone secretion, protein binding, lipid metabolic, fatty acid metabolic immune system process, and inflammatory response. Conclusion TXL has effects on inhibiting atherosclerosis development and stablizing plaque. The comprehensive mechanisms, in addition to inflammation and lipid metabolism, might also involve cell physical function, hormone secretion, protein binding, and immune response process.