Prevention and Treatment of Rheumatoid Arthritis Using Bone‐Targeted Angiotensin Peptide in Rats

Abstract

IntroductionThe precise etiology of Rheumatoid Arthritis (RA) remains uncertain; however, it has been shown that inflammation is responsible for activation of the renin–angiotensin system (RAS) which has been implicated in the pathogenesis and complications of RA. The main effectors of the RAS are Ang II and Ang 1‐7 which produced by Ang converting enzyme (ACE) and ACE2, respectively. Ang II is implicated in the up‐regulation of pro‐inflammatory cytokines through AT1R and contributed to the pathogenesis of RA. On the other hand, Ang 1‐7, counteract the inflammatory effects of Ang II by binding to Mas receptor and exerting anti‐inflammatory effects in experimental models of arthritis in rodent. Biological activity of Ang 1‐7 is hampered by its short half‐life due to rapid degradation by peptidases. We developed a novel bone‐seeking Ang 1‐7 conjugate (Ang Conj) and hypothesized that this novel approach will prolong half‐life and provide sustained plasma level to impose anti‐inflammatory activity. Since joint bone is the most common tissue impacted by RA, the rationale of this proposal was that, targeting of the bone with Ang Conj., as an anti‐inflammatory agent, could effectively control the signs and symptoms of arthritis.MethodsOn day one, for induction of adjuvant arthritis (AA), male Sprague Dawley rats were injected at the tail base with 0.2 mL of 50 mg/mL Mycobacterium butyricum. Arthritic animals were divided into 4 groups and treated with saline, Ang II, Ang 1‐7 and Ang Conj. A group of healthy rats received vehicle as control group. Preventive and treatment groups subcutaneously received 200 μg/kg equitant dose daily from day one for 3 weeks or after emergence of arthritis for 1 week, respectively. Animals were monitored daily for their body weight, paw and joint diameters. Animals were then euthanized, plasma/tissues were harvested and analyzed for plasma nitric oxide (NO), and the RAS components.ResultsOur results were in concert with previous reports concerning effects of inflammation on the RAS. AA presented itself by significant reduction in percent body weight gain, increased in paws, joints swelling and NO level, and reduced ACE2/ACE ratio. Administration of Ang 1‐7 or Ang Conj restored body weight gain, diminished the swelling of paws and joints and reduce plasma NO level in both treatment and preventive regimen. Consequently, the reduced ACE2/ACE balance was also restored by Ang 1‐7 and Ang Conj treatment.ConclusionThis result indicates that the prolongation of biological half‐life of Ang 1‐7 through injection of Ang Conj. exerts its anti‐inflammatory action by restoration of ACE2/ACE ratio which can augment the RAS major anti‐inflammatory component i.e. Ang 1‐7. This approach offers an effective strategy and an alternative option for management of RA patients and suggests a cardioprotective potential for this conjugate in management of inflammatory disease conditions such as RA.Support or Funding InformationStartup fund from College of Pharmacy, Idaho State UniversityPlasma nitric oxide levels in control and arthritic rats treated with Ang1‐7 or Ang1‐7 Conj.Figure 1Cardiac ACE2/ACE ratio and Mas receptor expression after treatment of control and arthritic rats with Ang 1‐7 or Ang Conj.Figure 2