Peng Zhong1, Gaofeng Zeng2, ChangCheng Lei2, Guoping Tian2, Shao Ouyang2, Fangyao Liu2, Jianye Peng3. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, Hubei, PR China. 2. Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, The Second Affiliated Hospital of the University of South China, Jiefang Road 30, Hengyang, 421000, Hunan, PR China. 3. Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, The Second Affiliated Hospital of the University of South China, Jiefang Road 30, Hengyang, 421000, Hunan, PR China. Electronic address: pengshu1234@163.com.
Abstract
BACKGROUND: Ciliary neurotrophic factor (CNTF), which is a neural peptide, has been reported to confer cardioprotective effects. However, whether CNTF-based gene therapy could prevent cardiac remodelling remains incompletely clear. In this study, we used adeno-associated viral vector serotype 9 (AAV9)-based cardiac gene therapy to test the effects of CNTF overexpression on adverse ventricular remodelling in angiotensin II (Ang II)-infused mice. METHODS: First, AAV9-EGFP and AAV9-CNTF constructs were generated with virus concentration at 5 × 1012 vg/ml. Next, postnatal (P3-P10) mice with C57BL/6J background were administered with 5 × 1011 vg of AAV9 recombinant genome diluted in 50 μl of saline, and delivered through intraperitoneal injection. Implantation of osmotic minipumps was performed in 8-week-old male mice and human Ang II solution was administrated in the mice subcutaneously for 14 days through the pumps. Finally, we evaluated the effects of CNTF overexpression on mouse cardiac function, hypertrophy and fibrosis, as well as investigated the possible mechanisms. RESULTS: Our data showed that CNTF overexpression in mouse cardiomyocytes prevents cardiac hypertrophy and fibrosis induced by chronic Ang II stimulation. Mechanistic study found that CNTF overexpression upregulated NFE2-related factor 2 (Nrf2) antioxidant pathway, coupled with decreased ROS level in the cardiac tissues. Additionally, inflammatory cytokines were found to be reduced upon cardiac CNTF overexpression in response to chronic Ang II stimulation. CONCLUSIONS: Altogether, these results provide further evidence that CNTF can alleviate the condition of cardiac remodelling induced by chronic Ang II stimulation. Therefore, our results suggest a potential therapeutic role of CNTF in cardiac pathological remodelling.
BACKGROUND:Ciliary neurotrophic factor (CNTF), which is a neural peptide, has been reported to confer cardioprotective effects. However, whether CNTF-based gene therapy could prevent cardiac remodelling remains incompletely clear. In this study, we used adeno-associated viral vector serotype 9 (AAV9)-based cardiac gene therapy to test the effects of CNTF overexpression on adverse ventricular remodelling in angiotensin II (Ang II)-infused mice. METHODS: First, AAV9-EGFP and AAV9-CNTF constructs were generated with virus concentration at 5 × 1012 vg/ml. Next, postnatal (P3-P10) mice with C57BL/6J background were administered with 5 × 1011 vg of AAV9 recombinant genome diluted in 50 μl of saline, and delivered through intraperitoneal injection. Implantation of osmotic minipumps was performed in 8-week-old male mice and humanAng II solution was administrated in the mice subcutaneously for 14 days through the pumps. Finally, we evaluated the effects of CNTF overexpression on mouse cardiac function, hypertrophy and fibrosis, as well as investigated the possible mechanisms. RESULTS: Our data showed that CNTF overexpression in mouse cardiomyocytes prevents cardiac hypertrophy and fibrosis induced by chronic Ang II stimulation. Mechanistic study found that CNTF overexpression upregulated NFE2-related factor 2 (Nrf2) antioxidant pathway, coupled with decreased ROS level in the cardiac tissues. Additionally, inflammatory cytokines were found to be reduced upon cardiac CNTF overexpression in response to chronic Ang II stimulation. CONCLUSIONS: Altogether, these results provide further evidence that CNTF can alleviate the condition of cardiac remodelling induced by chronic Ang II stimulation. Therefore, our results suggest a potential therapeutic role of CNTF in cardiac pathological remodelling.