Ciliary neurotrophic factor overexpression protects the heart against pathological remodelling in angiotensin II-infused mice

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 x 10(12) vg/ml. Next, postnatal (P3-P10) mice with C57BL/6J background were administered with 5 x 10(11) vg of AAV9 recombinant genome diluted in 50 ml 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 over expression 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. (c) 2021 Elsevier Inc. All rights reserved.