Abstract 039: Oral Delivery of Angiotensin Converting Enzyme2 and Angiotensin-(1-7) Bioencapsulated in Plant Cells Attenuates Pulmonary Hypertension
Rationale: Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin converting enzyme2 (ACE2) and its enzymatic product, angiotensin-(1-7) [Ang-(1-7)] contribute to the pathogenesis of pulmonary hypertension (PH). However, long-term repetitive delivery of ACE2 or Ang-(1-7) would require enhanced protein stability and ease of administration to improve patient compliance.
Objective: To develop a low-cost oral delivery system for ACE2 and Ang-(1-7), and demonstrate their therapeutic efficacy in an experimental model of PH.
Methods: We have taken advantage of transplastomic technology, which enables chloroplasts to generate high levels of therapeutic proteins within plant leaves. Transplastomic plants expressing ACE2 or Ang-(1-7) were created using biolistic delivery of chloroplast vectors. Male rats were given a single subcutaneous injection of monocrotaline (MCT, 50mg/Kg) to induce PH. Oral gavage of the frozen powdered leaves (500mg in phosphate buffered saline) expressing either ACE2 or Ang-(1-7) was performed twice daily for 4-weeks in MCT rats.
Results: MCT injected rats exhibited marked increase in right ventricular systolic pressure (RVSP; Control: 33±1mmHg; MCT: 89±4mmHg),signifying development of PH, which was associated with right ventricular hypertrophy (RVH; Control: 0.28±0.01; MCT: 0.63±0.03).However, oral feeding of MCT rats with bioencapsulated ACE2 or Ang-(1-7) showed significant decreases in RVSP (MCT+ACE2: 55±8mmHg, MCT+Ang-(1-7): 62±7mmHg ) and RVH (MCT+ACE2: 0.39±0.05, MCT+Ang-(1-7): 0.4±0.03). Similarly, echocardiography data revealed significant improvement in right heart function, along with enhanced pulmonary blood flow in MCT animals fed with ACE2 or Ang-(1-7). Furthermore, histological studies revealed considerable reduction in right ventricular fibrosis and pulmonary vessel wall thickness in ACE2 or Ang-(1-7) fed animals.These protective effects were associated with decreased inflammation.
Conclusion: Our study provides the first proof-of-concept for a novel low-cost oral ACE2 and Ang-(1-7) delivery system, using transplastomic technology that has significant clinical implications for treating PH.
Author Disclosures: V. Shenoy: None. K. Chul Kwon: None. A. Rathinasabapathy: None. S. Lin: None. G. Jin: None. C. Song: None. P. Shil: None. A. Nair: None. Y. Qi: None. Q. Li: None. J. Francis: None. M. Katovich: None. H. Daniell: None. M. Raizada: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.