Atherosclerosis-prone mice transfected with the longevity-associated variant (LAV) of BPIFB4 show reduced endothelial dysfunction and slowed atherogenic plaque progression compared with wild-type controls. These findings, published in the European Heart Journal, indicate that the favourable phenotype associated with long-living individuals and characterized by delayed or absent age-linked, atherosclerosis-related cardiovascular disease can be transferred to animal models via LAV-BPIFB4 gene therapy.
Age is a major risk factor for the development of atherosclerosis. The LAV in BPI fold-containing family B member 4 (BPIFB4) is enriched in long-living individuals and has previously been shown to improve endothelial function when transferred to old mice via gene therapy. In addition, LAV-BPIFB4 is thought to exert immunomodulatory activity, potentially via a CXC-chemokine receptor 4 (CXCR4)-dependent mechanism. “Thus, we adopted a model of atherosclerosis (a potential target of CXCR4 modulators) to evaluate the therapeutic effects of LAV-BPIFB4 in this setting and to determine if this effect was mediated by CXCR4,” comment Carmine Vecchione and Annibale Puca, lead investigators of the study.
LAV-BPIFB4, wild-type-BPIFB4 or an empty vector were delivered via adeno-associated viral transfer into Apoe–/– mice fed a high-fat diet. Mesenteric and femoral arteries taken from Apoe–/– mice overexpressing LAV-BPIFB4 showed diminished endothelial dysfunction compared with wild-type mice. This protective effect was completely abolished by treatment with AMD3100, a non-peptide antagonist of CXCR4. Furthermore, LAV-BPIFB4 gene therapy halted the formation of vascular plaques and reduced macrophage infiltration. These atheroprotective effects were again abolished by co-treatment with AMD3100.
At the immunological level, when autologous macrophages from patients with atherosclerosis were conditioned in vitro with a human recombinant LAV-BPIFB4 protein, the macrophages were polarized towards an anti-inflammatory M2 phenotype in a CXCR4-dependent manner. LAV-BPIFB4 reduced the inflammatory milieu within the vessels and improved endothelial-mediated vasorelaxation.
LAV-BPIFB4 gene therapy halted the formation of vascular plaques and reduced macrophage infiltration
Taken together, these findings demonstrate the efficacy of LAV-BPIFB4 gene therapy in reducing the atherogenic process. “Changes in immunological profile observed after gene therapy with LAV-BPIFB4 makes this approach a potential cure for a broad range of cardiovascular diseases,” concludes Vecchione.
Puca, A. A. et al. Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehz459 (2019)
Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018)
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Huynh, K. Longevity-associated gene variant halts progression of atherosclerosis. Nat Rev Cardiol 16, 516 (2019). https://doi.org/10.1038/s41569-019-0243-9