Potassium dehydroandrographolide succinate regulates the MyD88/CDH13 signaling pathway to enhance vascular injury-induced pathological vascular remodeling

Abstract

Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.

Keywords

Potassium dehydroandrographolide succinate / Smooth muscle cell / Myeloid differentiation factor 88 / T-cadherin / Pathological vascular remodeling

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Funding

National Natural Science Foundation of China(81741007)

National Natural Science Foundation of China(81870363)

Science & Technology Departments of Sichuan Province(2020JDTD0025)

Grant from Chengdu University of Traditional Chinese Medicine(008066)

Grant from Chengdu University of Traditional Chinese Medicine(030038199)

Grant from Chengdu University of Traditional Chinese Medicine(BJRC2018001/030041023)

Grant from Chengdu University of Traditional Chinese Medicine(030041224)

Grant from Chengdu University of Traditional Chinese Medicine(ZKYY2004/030055180)

Grant from Chengdu University of Traditional Chinese Medicine(242030016)