title: Recombinant AAV-PR39-mediated hypoxia-inducible factor 1α gene expression attenuates myocardial infarction.
abstract: PR39 is an angiogenic masterswitch protein, belonging to the second generation of angiogenic growth factors. However, the role of recombinant adeno-associated virus (AAV) carrying the PR39 fusion gene (AAV-PR39) in acute myocardial infarction remains unclear. Therefore, in this study, we investigated the role of AAV-PR39 in an experimental animal model of acute myocardial infarction. The PR39 gene was fused with the transmembrane peptide, TAT, 6xHis‑tag and NT4 signal sequences. AAV-PR39 was then obtained by calcium phosphate co-precipitation. A total of 18 healthy Chinese mini pigs were randomly divided into an experimental groups (the AAV-PR39-treated group) and a control group [phosphated-buffered saline (PBS)-treated group]. Following the induction of myocardial infarction, enhanced 3.0T MR imaging was performed to observe the changes in myocardial signal intensity at 0 h, 1, 2 and 3 weeks. The expression of hypoxia-inducible factor‑1α (HIF-1α) in the myocardial tissues was determined by SABC immunohistochemistry. In addition, in vitro experiments using CRL-1730 endothelial cells transfected with AAV vector containing NT4-TAT-His-PR39 revealed that the AAV-PR39-treated group had a significantly higher expression of HIF-1α compared with the control group. Moreover, PR39 regulated the HIF-1α-induced expression of angiogenic growth factors. Under hypoxic conditions, the anti-apoptotic effects in the AAV-PR39 group were more pronounced than those observed in the control (PBS-treated) group. In vivo, the enforced expression of recombinant PR39 elevated the level of HIF-1α under hypoxic conditions and decreased the size of the infarcted areas by upregulating the expression of HIF-1α in the areas surrounding the infarct area. Taken together, our data demonstrate that the recombinant AAV-PR39-mediated HIF-1α expression attenuates myocardial infarction, indicating that AAV-PR39 may serve as a novel therapeutic agent for the treatment of myocardial infarction.
authors.affiliation: Department of Radiology, Xijing Hospital of the Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Yuewen
authors.initials: Y
authors.lastname: Hao
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Nie
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Zhenwu
authors.initials: Z
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Xuexin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000628:therapy*; D009206:Myocardium / Q000166:cytology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
chemical_list: D023181:Antimicrobial Cationic Peptides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; C072212:PR 39