Abstract
Inflammation is a key etiologic component in atherogenesis. Previously we demonstrated that adeno-associated virus (AAV) 2/8 gene delivery of Netrin1 inhibited atherosclerosis in the low density lipoprotein receptor knockout mice on high-cholesterol diet (LDLR-KO/HCD). One important finding from this study was that FOXP3 was strongly up-regulated in these Netrin1-treated animals, as FOXP3 is an anti-inflammatory gene, being the master transcription factor of regulatory T cells. These results suggested that the FOXP3 gene might potentially be used, itself, as an agent to limit atherosclerosis. To test this hypothesis AAV2/8 (AAV)/hFOXP3 or AAV/Neo (control) gene therapy virus were tail vein injected into the LDLR-KO/HCD animal model. It was found that hFOXP3 gene delivery was associated with significantly lower HCD-induced atherogenesis, as measured by larger aortic lumen cross sectional area, thinner aortic wall thickness, and lower aortic systolic blood velocity compared with Neo gene-HCD-treated controls. Moreover these measurements taken from the hFOXP3/HCD-treated animals very closely matched those measurements taken from the normal diet (ND) control animals. These data strongly suggest that AAV/hFOXP3 delivery gave a robust anti-atherosclerosis therapeutic effect and further suggest that FOXP3 be examined more stringently as a therapeutic gene for clinical use.
Highlights
Inflammation is known to be a key regulatory process that is common denominator among several risk factors for atherosclerosis, in addition to accompanying and associated altered arterial biology [1, 2]
adenoassociated virus (AAV) vector construction and virus generation We directly addressed the hypothesis that hFOXP3 gene delivery can inhibit atherosclerosis by using AAV2/8 [AAV2 inverted terminal repeats (ITR) DNA combined with the AAV serotype 8 capsid] gene delivery
AAV vectors and animal treatments We directly addressed the hypothesis that hFOXP3 gene delivery can inhibit atherosclerosis by using AAV2/8 [AAV2 inverted terminal repeats (ITR) DNA combined with the AAV serotype 8 capsid] gene delivery
Summary
Inflammation is known to be a key regulatory process that is common denominator among several risk factors for atherosclerosis, in addition to accompanying and associated altered arterial biology [1, 2]. We recently published a study that demonstrated that AAV/Netrin systemic gene delivery was able to inhibit atherosclerosis in LDLR-KO mice on HCD [13] This was shown by high resolution ultrasound (HRUS) measurements of aortic lumen cross-sectional area, wall thickness, and systolic blood velocity. Upon analysis of the expression of various genes by Q-PCR we discovered that both Forkhead box P3’s (FOXP3) and CD25 expression were strongly up-regulated in the AAV/Netrin1-treated animals [13]. Both FOXP3 and CD25 are hallmark markers of regulatory T cells (Treg). The exact mechanism by which FOXP3 and CD25 are up-regulated by Netrin in aortas challenged with HCD remains to be determined
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