Lymphatic dysfunction plays a critical role in the development of atherosclerotic plaques, and targeting lymphatic regulation offers promising strategies for preventing and treating atherosclerosis (AS). This study aims to identify key genes influencing AS in lymphatic endothelial cells (LECs) followed by validation, and to explore potential intervention targets for AS treatment.

Single-cell data from the GEO database and Mendelian randomization was employed to identify genes in LECs that may either exacerbate or protect against AS. AS mouse models were established, followed by the assessment of key gene expression in lymphatic vessels within the plaque adventitia. In vitro, LECs were manipulated by silencing or overexpressing key genes to investigate the signaling pathways and mechanisms through which genes influence lymphangiogenesis.

Human carotid plaque data via the GEO database revealed that LEC-specific genes are closely associated with vasculogenesis, cell migration, and inflammatory responses during AS. Mendelian randomization analysis identified CD74 as a promoter of AS progression. In vivo experiments revealed a significant upregulation of CD74 expression during AS. Correlation analysis of CD74 in LECs with inflammatory genes from the GEO database, along with the in vitro construction of CD74 silencing and overexpression models in LECs, revealed the critical role of CD74 in the inflammatory response in AS. Gene correlation analysis and experimental validation revealed that CD74 promotes LEC pyroptosis through the NLRP3/SYK pathway. Additionally, in vitro results demonstrated that CD74 impairs lymphangiogenesis by inducing pyroptosis.

This study has identified the key gene CD74 in LECs that influence the progression of AS. Moreover, during AS, CD74 mediates NLRP3/SYK-dependent LEC pyroptosis, thereby inhibiting lymphangiogenesis and exacerbating the inflammatory response. These findings provide a novel molecular mechanism by which CD74 disrupts lymphatic function and accelerates AS progression, offering potential avenues for intervention in AS.

It is controversial whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) have a potentially beneficial role in the respiratory system. This study investigated the association between ACEI/ARB medications and respiratory-related mortality in hypertensive patients in a real-world nationally representative cohort.

This was a retrospective analysis based on a prospective cohort study. A total of 10,530 patients with hypertension aged ≥ 20 years were included. The data was extracted from the US National Health and Nutrition Examination Survey during 1988–1994 and 1999–2006. The study was approved by the Institutional Review Boards. Moreover, inform concent was taken form all the participants.

Overall, 27.7% (n = 2920) patients took ACEI/ARB agents. During a median follow-up of 12.4 years, 278 individuals died of respiratory disease, including chronic lower respiratory disease (n = 155) and influenza or pneumonia (n = 123). Compared with the patients without ACEI/ARB use, those taking ACEI/ARB were not associated with respiratory-specific mortality in a multivariable-adjusted Cox model. After 1: 1 matching, taking ACEI/ARB was also not related to respiratory mortality (Hazard ratio (HR) = 1.07, 95% CI: 0.79–1.43), influenza- or pneumonia-related (HR = 1.00, 95% CI: 0.65–1.54) and chronic pulmonary mortality (HR = 1.13, 95% CI: 0.75–1.69). After separating ACEI and ARB from anti-hypertensive medications, those associations remained unchanged.

We discovered no significant link between ACEI or ARB medication and pulmonary-related mortality in hypertensive patients. In hypertensive patients, standard ACEI/ARB administration may have little effect on the respiratory system.