Christine Lannon

Introduction. Aortic dissection (AD) involves a tear in the intimal layer of the aorta, allowing blood to flow into the medial layer and create a false lumen at risk for rupturing.^1,2,3 Type B aortic dissection (TBAD) occurs in an area other than the ascending aorta and has a 13% mortality rate at 30 days.¹  One cause of intimal tearing is an inflammatory response,¹ in which angiotensin II promotes macrophage infiltration into the medial layer.³ Activated macrophages then secrete IL-6, which activates the JAK/STAT3 pathway. Signal transducer and activator of transcriptome 3 (STAT3) acts as a transcriptional activator of pro-inflammatory genes.³ The current treatment plan for TBAD is unclear. Complicated cases may involve endovascular stenting, while uncomplicated cases require aggressive medical management to lower the blood pressure and heart rate¹. Although this latter treatment option lowers the aortic wall stress, its inability to address the prevention or repair of aortic degradation demonstrates the need for new therapies. Methods. Socs3, the negative feedback inhibitor of STAT3, was selectively deleted in the macrophages⁴ or smooth muscle cells⁵ of mice, producing mSocs3-KO and smSocs3-KO mice, respectively. Aortic dissection was induced. Immunohistochemical staining, flow cytometry, and western blotting of aortic tissue was performed.^4,5 A liposome, modified with monocyte plasma membrane for AD homing, was co-loaded with Celecoxib and Curcumin, which shows STAT3 inhibitory functions.⁶ The liposome was tested in a macrophage transwell assay and chronic AD mouse model.⁶ Results. STAT3 activation (pSTAT3) was increased at the site of aortic disruption in both wild type and mSocs3-KO mice; however, the mSocs3-KO macrophage population showed a 2:1 skewed differentiation towards the destructive M1 phenotype.⁴ The smSocs3-KO mice exhibited smaller lesion lengths, increased contractile and synthetic smooth muscle cell phenotypes, and increased adventitial fibroblasts to reinforce the tensile strength of the vessel.⁵ The modified liposome treatment exhibited decreased macrophage migration and STAT3 activation in vitro.⁶ Furthermore, the chronic AD mouse model showed prolonged survival rates and STAT3 inhibition with modified liposome treatment.⁶ Conclusion. STAT3 activation produces a destructive response in macrophages and a protective response in smooth muscle cells.^4,5 This dual role demonstrates the importance of targeted STAT3 therapy. The macrophage-targeted liposome shows promise for a TBAD nanotherapy involving targeted inhibition of STAT3 in the AD macrophages. Further studies should analyze the AD macrophage phenotypes after treatment and compare the liposome to current therapies.

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3. Aoki, H., Majima, R., Hashimoto, Y., Hirakata, S., & Ohno-Urabe, S. (2021). Ying and Yang of Stat3 in pathogenesis of aortic dissection. Journal of cardiology, 77(5), 471–474. https://doi.org/10.1016/j.jjcc.2020.10.010
4. Ohno-Urabe, S., Aoki, H., Nishihara, M., Furusho, A., Hirakata, S., Nishida, N., Ito, S., Hayashi, M., Yasukawa, H., Imaizumi, T., Akashi, H., Tanaka, H., & Fukumoto, Y. (2018). Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection. Journal of the American Heart Association, 7(2), e007389. https://doi.org/10.1161/JAHA.117.007389
5. Hirakata, S., Aoki, H., Ohno-Urabe, S., Nishihara, M., Furusho, A., Nishida, N., Ito, S., Hayashi, M., Yasukawa, H., Imaizumi, T., Hiromatsu, S., Tanaka, H., & Fukumoto, Y. (2020). Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice. JACC. Basic to translational science, 5(2), 126–144. https://doi.org/10.1016/j.jacbts.2019.10.010
6. Liu, J., Yang, Y., Liu, X., Widjaya, A. S., Jiang, B., & Jiang, Y. (2021). Macrophage-biomimetic anti-inflammatory liposomes for homing and treating of aortic dissection. Journal of controlled release : official journal of the Controlled Release Society, 337, 224–235. https://doi.org/10.1016/j.jconrel.2021.07.032