Abstract
Vascular smooth muscle cell (VSMC) proliferation and migration are vital to atherosclerosis (AS) development and plaque rupture. MicroRNA-377-3p (miR-377-3p) has been reported to inhibit AS in apolipoprotein E knockout (ApoE−/−) mice. Herein, the mechanism underlying the effect of miR-377-3p on alleviating AS is explored. In vivo experiments, ApoE−/− mice were fed with high-fat diet (HFD) to induce AS and treated with miR-377-3p agomir or negative control agomir (agomir-NC) on week 0, 2, 4, 6, 8, 10 after HFD feeding. MiR-377-3p was found to restore HFD-induced AS lesions and expressions of matrix metalloproteinase (MMP)-2, MMP-9, α-smooth muscle actin (α-actin) and calponin. In in vitro experiments, human VSMCs were tranfected with miR-377-3p agomir or agomir-NC, followed by treatment with oxidized low-density lipoprotein (ox-LDL). MiR-377-3p was observed to significantly inhibit ox-LDL-induced VSMC proliferation characterized by inhibited cell viability, expressions of proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E and cell cycle transition from G1 to S phase accompanied with less 5-Ethynyl-2′-deoxyuridine (EdU)-positive cells. Furthermore, MiR-377-3p significantly inhibited ox-LDL-induced VSMC migration characterized by inhibited wound closure and decreased relative VSMC migration. Besides, neuropilin2 (NRP2) was verified as a target of miR-377-3p. MiR-377-3p was observed to inhibit NRP2 expressions in vivo and in vitro. Moreover, miR-377-3p significantly inhibited MMP-2 and MMP-9 expressions in human VSMCs. Additionally, miR-377-3p-induced inhibition of VSMC proliferation and migration could be attenuated by NRP2 overexpression. These results indicated that miR-377-3p inhibited VSMC proliferation and migration via targeting NRP2. The present study provides an underlying mechanism for miR-377-3p-based AS therapy.
Highlights
Cardiovascular disease (CVD) is the underlying cause of all deaths in low- and middle-income countries [1]
high-fat diet (HFD) resulted in marked increases in matrix metalloproteinase (MMP)-2 and MMP-9 expressions (Figure 1C,D, P
After overexpression of NRP2, cell viability (Figure 5D, P
Summary
Cardiovascular disease (CVD) is the underlying cause of all deaths in low- and middle-income countries [1]. Atherosclerosis (AS), a chronic disease, is the primary cause of CVD, including coronary heart disease (CHD), cerebral infarction and peripheral arterial disease (PAD). Disorder of lipid metabolism is a risk factor for AS [2]. AS lesion is characterized by the accumulation of lipid and fibrous elements in the intima of artery and the thickening and hardening of artery walls [3]. In spite of the improvement in living standards and therapeutic strategies, AS-induced CVD continues to be the principal cause of global deaths and accounts for approximately 31% of all deaths worldwide (WHO, 2017). As a consequence, exploring the underlying mechanism of AS therapy is of vital importance for AS treatment
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