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Abstract
Background
Atherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent atorvastatin calcium (Ato) alleviates atherosclerosis by reducing plasma lipid and inflammatory factors. However, the low bioavailability of Ato limits its widespread use and clinical effectiveness. Curcumin (Cur), a natural polyphenol with antioxidation and anti-inflammation bioactivities, has potential anti-atherosclerosis activity and may reduce Ato-induced cytotoxicity.
Materials and methods
Liposomes modified using a targeting ligand (E-selectin-binding peptide) were prepared to co-deliver Ato and Cur to dysfunctional endothelial cells (ECs) overexpressing E-selectin. Molecules involved in the inhibition of adhesion (E-selectin and intercellular cell adhesion molecule-1 [ICAM-1]) and inflammation (IL-6 and monocyte chemotactic protein 1 [MCP-1]) in human aortic endothelial cells were evaluated using real-time quantitative PCR, flow cytometry, and immunofluorescence staining. The antiatherosclerosis effects of liposomes co-loaded with Ato and Cur in vivo were evaluated using ApoE knockout (ApoE−/−) mice.
Results
Targeted liposomes delivered Ato and Cur to dysfunctional ECs, resulting in synergistic suppression of adhesion molecules (E-selectin and ICAM-1) and plasma lipid levels. Moreover, this treatment reduced foam cell formation and the secretion of inflammatory factors (IL-6 and MCP-1) by blocking monocyte migration into the intima. In addition, Cur successfully reduced Ato-inducible cytotoxicity.
Conclusion
Both in vitro and in vivo experiments demonstrated that cell-targeted co-delivery of Ato and Cur to dysfunctional ECs drastically reduces atherosclerotic lesions with fewer side effects than either Ato or Cur alone.
Supplementary material
Figure S1 Relative gene expression levels of E-selectin and ICAM-1 in human aortic endothelial cells stimulated with 1 µg/mL lipopolysaccharide for different periods of time (mean ± SD; n=3; *P<0.05 and #P<0.05 compared with that of 2 hours).
Acknowledgments
This work was supported by the National Key R&D Program of China (2016YFE0117100), National Basic Research Program of China (2015CB755500), the National Natural Science Foundation of China (21875289, 51373203, U1501243, 31530023), Natural Science Foundation of the Guangdong Province (2014A030312018, 2015A030313283, 2016A030313554), the Guangdong Innovative and Entrepreneurial Research Team Program (2013S086), the Guangdong-Hongkong Joint innovation Project (2016A050503026), the Project on the Integration of Industry, Education and Research of Guangdong Province (2013B090500094), the Major Project on the Integration of Industry, Education and Research of Guangzhou City (201704030123), and the Fundamental Research Funds for the Central Universities (16lgjc59 and 20162900031650004).
Disclosure
The authors report no conflicts of interest in this work.