Captopril Alleviates Chondrocyte Senescence in DOCA-Salt Hypertensive Rats Associated with Gut Microbiome Alteration.

Abstract

Gut microbiota is the key controller of healthy aging. Hypertension and osteoarthritis (OA) are two frequently co-existing age-related pathologies in older adults. Both are associated with gut microbiota dysbiosis. Hereby, we explore gut microbiome alteration in the Deoxycorticosterone acetate (DOCA)-induced hypertensive rat model. Captopril, an anti-hypertensive medicine, was chosen to attenuate joint damage. Knee joints were harvested for radiological and histological examination; meanwhile, fecal samples were collected for 16S rRNA and shotgun sequencing. The 16S rRNA data was annotated using Qiime 2 v2019.10, while metagenomic data was functionally profiled with HUMAnN 2.0 database. Differential abundance analyses were adopted to identify the significant bacterial genera and pathways from the gut microbiota. DOCA-induced hypertension induced p16INK4a+ senescent cells (SnCs) accumulation not only in the aorta and kidney (p < 0.05) but also knee joint, which contributed to articular cartilage degradation and subchondral bone disturbance. Captopril removed the p16INK4a + SnCs from different organs, partially lowered blood pressure, and mitigated cartilage damage. Meanwhile, these alterations were found to associate with the reduction of Escherichia-Shigella levels in the gut microbiome. As such, gut microbiota dysbiosis might emerge as a metabolic link in chondrocyte senescence induced by DOCA-triggered hypertension. The underlying molecular mechanism warrants further investigation.