Title

Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension

Authors

Vinayak Shenoy, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Kwang-Chul Kwon, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Anandharajan Rathinasabapathy, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Shina Lin, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Guiying Jin, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Chunjuan Song, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Pollob Shil, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Anand Nair, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Yanfei Qi, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Qiuhong Li, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Joseph Francis, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Michael J. Katovich, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.).
Henry Daniell, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.). hdaniell@upenn.edu mraizada@ufl.edu.
Mohan K. Raizada, Departments of Pharmacodynamics (V.S., A.R., M.J.K.), Physiology and Functional Genomics (C.S., Y.Q., M.K.R.), and Ophthalmology (P.S., Q.L.), University of Florida, Gainesville; Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia (K.-C.K., S.L., G.J., H.D.); and Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge (A.N., J.F.). hdaniell@upenn.edu mraizada@ufl.edu.

Document Type

Article

Publication Date

12-1-2014

Abstract

Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin-converting enzyme 2 (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. Chloroplast expression of therapeutic proteins enables their bioencapsulation within plant cells to protect against gastric enzymatic degradation and facilitates long-term storage at room temperature. Besides, fusion to a transmucosal carrier helps effective systemic absorption from the intestine on oral delivery. We hypothesized that bioencapsulating ACE2 or Ang-(1-7) fused to the cholera nontoxin B subunit would enable development of an oral delivery system that is effective in treating PH. PH was induced in male Sprague Dawley rats by monocrotaline administration. Subset of animals was simultaneously treated with bioencapsulaed ACE2 or Ang-(1-7) (prevention protocol). In a separate set of experiments, drug treatment was initiated after 2 weeks of PH induction (reversal protocol). Oral feeding of rats with bioencapsulated ACE2 or Ang-(1-7) prevented the development of monocrotaline-induced PH and improved associated cardiopulmonary pathophysiology. Furthermore, in the reversal protocol, oral ACE2 or Ang-(1-7) treatment significantly arrested disease progression, along with improvement in right heart function, and decrease in pulmonary vessel wall thickness. In addition, a combination therapy with ACE2 and Ang-(1-7) augmented the beneficial effects against monocrotaline-induced lung injury. Our study provides proof-of-concept for a novel low-cost oral ACE2 or Ang-(1-7) delivery system using transplastomic technology for pulmonary disease therapeutics.

Publication Source (Journal or Book title)

Hypertension (Dallas, Tex. : 1979)

First Page

1248

Last Page

59

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