AIMS: Overexpression of therapeutic genes with potential disease-limiting effects, specifically at the site of inflammation, remains a major clinical challenge. In this study, we investigate the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of the anti-inflammatory mediators interleukin (IL)-10 and a dominant-negative inhibitor of monocyte chemoattractant protein-1 (MCP1-7ND) on prevention of autoimmune myocarditis. METHODS AND RESULTS: Autoimmune myocarditis was induced by immunizing A/J mice with subcutaneous injection of 120 µg cardiac troponin I (cTnI) on Days 0, 7, and 14. Two weeks prior to initial immunization, each mouse received a single systemic dose of 10(12) AAV9 vectors carrying the coding sequence of IL-10 or MCP1-7ND transcriptionally targeted to the heart. Mice were sacrificed 28 days after initial immunization for further analysis. Only expression of IL-10 resulted in a highly significant decrease in myocardial inflammation and fibrosis, as well as an increased ejection fraction compared with controls. Further analyses of cytokine profiles of cTnI-stimulated splenocytes from IL-10 and MCP1-7ND-treated mice revealed significant alterations compared with controls. In addition, transcript levels of chemokine receptor CCR4 and T-cell activation gene were significantly reduced in hearts of IL-10-treated mice as determined by quantitative real-time PCR. CONCLUSION: Our study suggests that cardiac expression of IL-10 with AAV9 vectors is a promising therapeutic approach for autoimmune myocarditis.
AIMS: Overexpression of therapeutic genes with potential disease-limiting effects, specifically at the site of inflammation, remains a major clinical challenge. In this study, we investigate the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of the anti-inflammatory mediators interleukin (IL)-10 and a dominant-negative inhibitor of monocyte chemoattractant protein-1 (MCP1-7ND) on prevention of autoimmune myocarditis. METHODS AND RESULTS:Autoimmune myocarditis was induced by immunizing A/J mice with subcutaneous injection of 120 µg cardiac troponin I (cTnI) on Days 0, 7, and 14. Two weeks prior to initial immunization, each mouse received a single systemic dose of 10(12) AAV9 vectors carrying the coding sequence of IL-10 or MCP1-7ND transcriptionally targeted to the heart. Mice were sacrificed 28 days after initial immunization for further analysis. Only expression of IL-10 resulted in a highly significant decrease in myocardial inflammation and fibrosis, as well as an increased ejection fraction compared with controls. Further analyses of cytokine profiles of cTnI-stimulated splenocytes from IL-10 and MCP1-7ND-treated mice revealed significant alterations compared with controls. In addition, transcript levels of chemokine receptor CCR4 and T-cell activation gene were significantly reduced in hearts of IL-10-treated mice as determined by quantitative real-time PCR. CONCLUSION: Our study suggests that cardiac expression of IL-10 with AAV9 vectors is a promising therapeutic approach for autoimmune myocarditis.
Authors: Peter Celec; Július Hodosy; Roman Gardlík; Michal Behuliak; Roland Pálffy; Marek Pribula; Peter Jáni; Ján Turňa; Katarína Sebeková Journal: Hum Gene Ther Date: 2012-01-26 Impact factor: 5.695
Authors: Prasad R Konkalmatt; Feng Wang; Bryan A Piras; Yaqin Xu; Daniel M O'Connor; Ronald J Beyers; Frederick H Epstein; Brian H Annex; John A Hossack; Brent A French Journal: J Gene Med Date: 2012 Sep-Oct Impact factor: 4.565
Authors: Li Yue-Chun; Zhang Teng; Zhou Na-Dan; Ge Li-Sha; Luo Qin; Guan Xue-Qiang; Lin Jia-Feng Journal: PLoS One Date: 2012-06-28 Impact factor: 3.240
Authors: Oliver Zimmermann; Jörg M Homann; Anna Bangert; Anna-Maria Müller; Georgi Hristov; Stefan Goeser; Juliane M Wiehe; Stefan Zittrich; Wolfgang Rottbauer; Jan Torzewski; Gabriele Pfitzer; Hugo A Katus; Ziya Kaya Journal: J Am Heart Assoc Date: 2012-12-19 Impact factor: 5.501