Naringenin Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cells Proliferation and Migration and Decreases Neointimal Hyperplasia in Balloon Injured Rat Carotid Arteries through Suppressing Oxidative Stress

The uncontrolled proliferation and migration of vascular smooth muscle cells is a critical step in the pathological process of restenosis caused by vascular intimal hyperplasia. Jujuboside B (JB) is one of the main biologically active ingredients extracted from the seeds of Zizyphus jujuba (SZJ), which has the properties of anti-platelet aggregation and reducing vascular tension. However, its effects on restenosis after vascular intervention caused by VSMCs proliferation and migration remain still unknown. Herein, we present novel data showing that JB treatment could significantly reduce the neointimal hyperplasia of balloon-damaged blood vessels in Sprague-Dawley (SD) rats. In cultured VSMCs, JB pretreatment significantly reduced cell dedifferentiation, proliferation, and migration induced by platelet-derived growth factor-BB (PDGF-BB). JB attenuated autophagy and reactive oxygen species (ROS) production stimulated by PDGF-BB. Besides, JB promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Notably, inhibition of AMPK and PPAR-γ partially reversed the ability of JB to resist the proliferation and migration of VSMCs. Taken as a whole, our findings reveal for the first time the anti-restenosis properties of JB in vivo and in vitro after the endovascular intervention. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation, and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway. These results indicate that JB might be a promising clinical candidate drug against in-stent restenosis, which provides a reference for further research on the prevention and treatment of vascular-related diseases.

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Mangiferin Inhibits PDGF-BB-Induced Proliferation and Migration of Rat Vascular Smooth Muscle Cells and Alleviates Neointimal Formation in Mice through the AMPK/Drp1 Axis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3119953 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Qi Wu ◽

Yuanyang Chen ◽

Zhiwei Wang ◽

Xin Cai ◽

Yanjia Che ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

Neointimal Formation ◽

Artery Ligation ◽

And Migration ◽

Proliferation And Migration

Mangiferin is a naturally occurring xanthone C-glycoside that is widely found in various plants. Previous studies have reported that mangiferin inhibits tumor cell proliferation and migration. Excessive proliferation and migration of vascular smooth muscle cells (SMCs) is associated with neointimal hyperplasia in coronary arteries. However, the role and mechanism of mangiferin action in neointimal hyperplasia is still unknown. In this study, a mouse carotid artery ligation model was established, and primary rat smooth muscle cells were isolated and used for mechanistic assays. We found that mangiferin alleviated neointimal hyperplasia, inhibited proliferation and migration of SMCs, and promoted platelets derive growth factors-BB- (PDGF-BB-) induced contractile phenotype in SMCs. Moreover, mangiferin attenuated neointimal formation by inhibiting mitochondrial fission through the AMPK/Drp1 signaling pathway. These findings suggest that mangiferin has the potential to maintain vascular homeostasis and inhibit neointimal hyperplasia.

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Abstract 22: Histone Deacetylase (HDAC) 4 Controls Neointimal Hyperplasia via Stimulating Proliferation and Migration of Vascular Smooth Muscle Cells

Hypertension ◽

10.1161/hyp.62.suppl_1.a22 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Tatsuya Usui ◽

Muneyoshi Okada ◽

Hideyuki Yamawaki

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

Cell Counting ◽

And Migration ◽

Proliferation And Migration

Histone deacetylases (HDACs) are transcriptional co-regulators. We have recently demonstrated that a class IIa HDAC, HDAC4 promotes reactive oxygen species (ROS)-dependent vascular smooth muscle inflammation and mediates the development of hypertension in spontaneously hypertensive rats. Pathogenesis of hypertension is in part modulated by vascular structural remodeling via proliferation and migration of vascular smooth muscle cells (SMCs). We thus examined whether HDAC4 controls SMCs proliferation and migration. In rat mesenteric arterial SMCs, small interfering RNA (siRNA) against HDAC4 inhibited platelet-derived growth factor (PDGF)-BB-induced SMCs proliferation as determined by a cell counting (51% inhibition, n=7) or bromodeoxyuridine incorporation assay (95% inhibition, n=6) and migration as determined by Boyden chamber assay (71% inhibition, n=3). Expression and activity of HDAC4 were increased by PDGF-BB (30% increase, n=5 and 170% increase, n=4, respectively). HDAC4 siRNA inhibited phosphorylation of p38 (69% inhibition, n=5) and heat shock protein (HSP) 27 (91% inhibition, n=5) and expression of cyclin D1 (58% inhibition, n=5) as measured by Western blotting. HDAC4 siRNA also inhibited PDGF-BB-induce ROS production as measured fluorometrically using 2’ 7’-dichlorofluorescein diacetate (77% inhibition, n=4) and nicotinamide adenine dinucleotide phosphate oxidase activity as measured by lucigenin assay (61% inhibition, n=4). A Ca 2+ /calmodulin (CaM)-dependent protein kinase (CaMK) II inhibitor, KN93 inhibited PDGF-BB-induced SMCs proliferation (58% inhibition, n=4) and migration (75% inhibition, n=3) as well as phosphorylation of HDAC4 (84% inhibition, n=4). In vivo, a class IIa HDACs inhibitor, MC1568 prevented neointimal hyperplasia in mice carotid ligation model (54% inhibition, n=6). MC1568 also inhibited increased activity of HDAC4 in the neointimal lesions. The present results for the first time demonstrate that HDAC4 controls PDGF-BB-induced SMCs proliferation and migration through activation of p38/HSP27 signals via ROS generation in a CaMKII-dependent manner, which may lead to the neointima hyperplasia in vivo.

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