The Causal Relationship between Chronic Obstructive Pulmonary Disease and Cardiovascular Diseases: Role of Systemic Inflammation and NF-κB/COX-2 Pathway

Abstract

Background Chronic Obstructive Pulmonary Disease (COPD) is a significant global health issue that often coexists with cardiovascular and cerebrovascular diseases. The aim of this study is to investigate the causal relationship between COPD and these diseases, with a focus on the role of systemic inflammation and the NF-κB/COX-2 pathway. Methods The Two-Sample Mendelian Randomization (TSMR) approach was used to analyze the genetic correlation between COPD and the risks of ischemic stroke (IS) and acute myocardial infarction (AMI) using data from several large biobanks. In addition, in vivo experiments with ApoE knockout mice and in vitro assays with primary mouse aorta endothelial cells were conducted to explore the role of the NF-κB/COX-2 pathway in COPD-related systemic inflammation. Results The MR analysis revealed a significant association between COPD and increased risks of IS (OR: 1.152) and AMI (OR: 1.001). In vivo findings showed exacerbated pulmonary dysfunction and atherogenesis in mice with both COPD and high-fat diet (HFD), with notable histological changes in lung and aortic tissues. Inflammatory markers and lipid profiles were significantly altered in these models. In vitro studies demonstrated that COPD-induced systemic inflammation impaired endothelial cell function. These changes were mitigated by inhibiting the NF-κB/COX-2 pathway. Conclusions This study provides strong evidence of a causal link between COPD and an elevated risk of cardiovascular diseases, mediated by systemic inflammation and the NF-κB/COX-2 pathway. These findings highlight the importance of addressing cardiovascular risks in COPD management and suggest that the NF-κB/COX-2 pathway could be a potential therapeutic target for reducing comorbid cardiovascular conditions in COPD patients.