Abstract
The proliferation and migration of vascular smooth muscle cells (VSMCs) play an essential role during the development of cardiovascular diseases (CVDs). While many factors potentially contribute to the abnormal activation of VSMCs, hyperglycemia is generally believed to be a major causative factor. On the other hand, FAM3B (named PANDER for its secretory form) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. FAM3B is co-secreted with insulin from the β-cell upon glucose stimulation and regulates glucose homeostasis. In the present study, we sought to determine the roles of FAM3B in the regulation of VSMC physiology, especially under the hyperglycemic condition. We found that FAM3B expression was induced by hyperglycemia both in vivo and in vitro. FAM3B knockdown inhibited, whereas FAM3B overexpression accelerated VSMC proliferation and migration. At the molecular level, FAM3B inhibited miR-322-5p expression, and enforced expression of miR-322-5p antagonized FAM3B-induced VSMC proliferation and migration, suggesting that FAM3B facilitated VSMC pathological activation via miR-322-5p. Taken together, FAM3B mediates high glucose-induced VSMC proliferation and migration via inhibition of miR-322-5p. Thus, FAM3B may therefore serve as a novel therapeutic target for diabetes-related CVDs.
Highlights
As is known, vascular smooth muscle cells (VSMCs) are plastic to change their morphology and the rates of proliferation and migration, perform contractile and synthetic functions
FAM3B undoubtedly plays an important role in the glucose homeostasis, it remains unknown whether it affects VSMC pathophysiological behaviors, especially the cell proliferation and migration, under hyperglycemic condition
Coincided with observations of the immunofluorescence staining, RT-qPCR analysis indicated that the mRNA expression levels of FAM3B in the VSMC layer was increased in a time-dependent manner when rats developed hyperglycemia (Fig. 1C)
Summary
Vascular smooth muscle cells (VSMCs) are plastic to change their morphology and the rates of proliferation and migration, perform contractile and synthetic functions. The phosphorylation of the extracellular signal regulated kinase (ERK) 1/2 and the progression of cell cycle are the common convergent points for the mitogenic signaling cascades[8] In this sense, inhibition of VSMC proliferation and migration has high value in the prevention and attenuation of related CVDs. While many factors potentially contribute to the development of atherosclerosis including abnormalities in plasma lipoproteins and blood pressure seen in diabetic patients, hyperglycemia has been recognized to be a major causative factor[9]. Glucose induces FAM3B gene expression via multiple signaling pathways that include Ca2+ protein kinase A (PKA), Ca2+ protein kinase C (PKC), ERK1/2, and cAMP-responsive element-binding protein (CREB) mechanisms Both phosphoinositide 3- kinase (PI3K)- and ROS-related pathways are involved as well[20]. We demonstrated for the first time that in response to glucose, FAM3B facilitates VSMC proliferation and migration, at least in part, by miR-322-5p inhibition
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