Track: Preclinical Development - Biomolecular - Translation - Novel Drug Modality/Novel Drug Delivery
Category: Poster Abstract
Bone-Targeted Angiotensin Peptide Therapy in Adjuvant Arthritic Rat: Impact on the Lung Renin-Angiotensin System Components
Purpose: Rheumatoid arthritis (RA) is a prevalent, chronic inflammatory and erosive joint diseases which affect as many as 1-2% of the population worldwide (1,2) RA is characterized by progressive joint inflammation and associated with excess morbidity and mortality from cardiovascular and pulmonary complications (3). The activated renin-angiotensin (RAS) plays an important role in the pathogenesis of inflammatory arthritis. The RAS is composed of two opposing axes with several components including Angiotensin Converting Enzyme (ACE) and ACE2 enzymes, Angiotensin II (Ang II) and Ang (1-7) peptides, and Ang II type 1 (AT1R) and Mas receptors. Ang II is implicated in the up-regulation of pro-inflammatory cytokines through AT1R and contributed to the pathogenesis of RA (4). On the other hand, Ang 1-7, counteract the inflammatory effects of Ang II by binding to Mas receptor and exerting anti-inflammatory effects. 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) with a prolonged half-life which upon systemic administration provides sustained plasma level of Ang 1-7 to impose an anti-inflammatory activity in different impacted tissues including the lung. Methods: On 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 preventive (PG) and ameliorating (AG) groups. Animals in subgroups injected subcutaneously with vehicle (saline), Ang II (PG only), Ang 1-7 or Ang Conj. The animal dosed with 200 µg/kg/day of equivalent peptide from day 1 for 3 weeks (PG) or after emergence of arthritis for 1 week (AG). Animals were monitored daily for their body weight, paw and joint diameters. At the end of experiment, animals were euthanized, plasma/tissues (lung) were harvested and analyzed for plasma nitric oxide (NO) and the RAS components using western blotting and LC/MS-MS analysis. Results: AA presented itself by significant reduction in percent body weight gain, increased in paws, joints swelling and NO level, and reduced ACE2/ACE and Ang1-7/AngII ratios in lung tissue. There was a significant correlation between plasma NO level and tissue ACE2/ACE and Ang1-7/AngII ratios. 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 AG and PG (Fig. 1). Consequently, the reduced lung ACE2/ACE ratio was also restored by Ang 1-7 and Ang Conj treatment (Fig. 2). Conclusion: This result indicates that inflammation has significant impact on the lung RAS system and using a stable formulation of Ang 1-7 was able to augment tissue protective arm of the RAS to impose its anti-inflammatory action by restoration of ACE2/ACE ratio and Ang1-7/Ang II. This approach offers an effective strategy and an alternative option for management of RA patients and suggests a tissue protective potential for this conjugate in management of inflammatory lung disease conditions.
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