Effects of Blood Pressure and Antihypertensive Drugs on Rheumatoid Arthritis: A Mendelian Randomization, Network Pharmacology, and Experimental Validation.

BACKGROUND

We conducted a Mendelian randomization study in conjunction with a network pharmacology study to provide an analytical elucidation of the potential causal relationship between blood pressure and antihypertensive drugs and rheumatoid arthritis.

METHODS

First, a Mendelian randomization analysis was performed using large-scale GWAS data to assess the causal associations of systolic/diastolic blood pressure and 12 antihypertensive drug classes with rheumatoid arthritis. The analytical model of inverse variance weighting was primarily utilized. Second, we constructed a "drug-component-target-disease" regulatory network graph and analyzed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment. Third, we validated some of the mined data through molecular docking technology using BIOVIA Discovery Studio 2019. Finally, animal experiments were performed to verify.

RESULTS

The results indicated that elevated diastolic blood pressure was significantly associated with an increased risk of rheumatoid arthritis. Among antihypertensive drugs, adrenergic neuron blockers, central antihypertensives, and potassium-sparing diuretics/aldosterone antagonists reduced the risk of rheumatoid arthritis. Sensitivity analyses demonstrated the absence of pleiotropy or heterogeneity. In addition, after network pharmacology research, the molecular docking of its active ingredients with their targets was carried out, and the link potential was relatively ideal. Construction of a rat model of rheumatoid arthritis, Western blotting assay for Endothelin Receptor Type B (EDNRB), Angiotensin II Receptor Type (AGTR) expression level. Western blot analysis showed elevated EDNRB and AGTR levels in the model group, with spironolactone group significantly reducing these levels, though still higher than methotrexate group.

CONCLUSION

The findings of our study indicate that elevated diastolic blood pressure is associated with an increased risk of rheumatoid arthritis. However, three classes of antihypertensive medications, namely adrenergic neuron blockers, central antihypertensives, and potassium-sparing diuretics and aldosterone antagonists, have been demonstrated to exert beneficial effects on rheumatoid arthritis.