Abstract
BackgroundAlthough vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2–3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated.MethodsCIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo.ResultsSignificant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice.ConclusionCI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.
Highlights
Rheumatoid arthritis (RA) is a common inflammatory arthritis and significant cause of disability due to permanent joint destruction and deformity [1]
Expression of vascular endothelial growth factor-A (VEGF) and CD31 in the synovium of healthy human subjects and rheumatoid arthritis (RA) patients Since VEGF-induced angiogenesis has been reported to play an important role in the progression of RA, a type of inflammatory arthritis, we investigated VEGF and CD31 expression in human synovial membrane samples collected from de-identified age-matched (40–60 years) healthy human subjects (3 females and 3 males) who had undergone amputation due to injury and RA patients (3 females and 3 males) who underwent joint replacement surgery
Effect of Chebulinic acid (CI) on disease progression Compared with untreated control arthritic mice, mice orally treated with CI (50 mg/kg/day for 14 consecutive days) showed significantly inhibited collagen-induced arthritis (CIA) severity, as assessed by gross paw swelling (Fig. 2a), mean paw diameter (Fig. 2b, *p < 0.05), and mean articular index (Fig. 2c; *p < 0.05)
Summary
Rheumatoid arthritis (RA) is a common inflammatory arthritis and significant cause of disability due to permanent joint destruction and deformity [1]. As reports from oncology clinics indicate that hypertension is a major side effect of currently used anti-VEGF agents and because RA patients commonly present with hypertension, it would be prudent to identify an anti-VEGF antiangiogenic agent that does not increase blood pressure for the treatment of RA [10,11,12,13] In this respect, chebulinic acid (CI), a naturally occurring tannin, may be a molecule of interest, because we recently demonstrated that CI could significantly inhibit the proangiogenic effects of VEGF on human umbilical vein endothelial cells (HUVECs) [14]. The effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated
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