HIF-1 inhibition decreases systemic vascular remodelling diseases by promoting apoptosis through a hexokinase 2-dependent mechanism
HIF-1 inhibition decreases systemic vascular remodelling diseases by promoting apoptosis through a hexokinase 2-dependent mechanism
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DOI：
10.1093/cvr/cvq152
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发表时间：
2010-10-01
影响因子：
10.8
通讯作者：
Bonnet, Sebastien
中科院分区：
文献类型：
--
作者：
Lambert, Caroline M.;Roy, Melanie;Bonnet, Sebastien
血管重塑疾病的特征在于存在增殖性和抗血管平滑肌细胞（VSMC）。有证据表明，促增殖和抗凋亡状态的特征在于代谢重塑（具有超极化线粒体的糖酵解表型），其涉及Akt途径被循环生长因子激活。缺氧诱导因子-1（HIF-1）参与多种血管疾病的发生。由于这种转录因子参与了代谢反应，我们假设HIF-1的活性可能参与了动脉损伤后的血管重塑，我们的研究结果表明，生长因子，如血小板衍生生长因子（PDGF），激活了人颈动脉VSMC中的Akt通路（通过免疫印迹法测定）。该途径的激活增加了HIF-1的激活（通过免疫印迹法测量），导致VSMC糖酵解增加。己糖激酶2（HXK 2）的表达和线粒体活性，糖酵解的主要引发剂，在HIF-1激活过程中增加。VSMC中HXK 2的线粒体活性导致线粒体膜电位的超极化（通过四甲基罗丹明甲酯高氯酸盐测量）和细胞凋亡的抑制（通过TUNEL测定和3活性测量），这些作用被HIF-1抑制阻断。此外，HIF-1抑制也降低VSMC增殖（增殖细胞核抗原和Ki-67测定）。在体内，我们证明了局部抑制HIF-1，使用显性负HIF-1 α腺病毒构建，防止颈动脉损伤后remodeling.We建议，HIF-1是中央参与颈动脉重塑动脉损伤和局部抑制HIF-1可能是一种新的治疗策略，以防止颈动脉狭窄。
Vascular remodelling diseases are characterized by the presence of proliferative and apoptosis-resistant vascular smooth muscle cells (VSMC). There is evidence that pro-proliferative and anti-apoptotic states are characterized by metabolic remodelling (a glycolytic phenotype with hyperpolarized mitochondria) involving Akt pathway activation by circulating growth factors. Hypoxia-inducible factor-1 (HIF-1) is involved in different vascular diseases. Since this transcription factor is implicated in metabolic responses, we hypothesized that HIF-1 activity could be involved in vascular remodelling in response to arterial injury.Our findings indicate that growth factors, such as platelet-derived growth factor (PDGF), activate the Akt pathway (measured by immunoblot) in human carotid artery VSMC. Activation of this pathway increased HIF-1 activation (measured by immunoblot), leading to increased glycolysis in VSMC. Expression and mitochondrial activity of hexokinase 2 (HXK2), a primary initiator of glycolysis, are increased during HIF-1 activation. The mitochondrial activity of HXK2 in VSMC led to the hyperpolarization of mitochondrial membrane potential (measured by tetramethylrhodamine methyl-ester perchlorate) and the suppression of apoptosis (measured by TUNEL assay and 3 activity), effects that are blocked by HIF-1 inhibition. Additionally, HIF-1 inhibition also decreased VSMC proliferation (proliferating cell nuclear antigen and Ki-67 assays). In vivo, we demonstrate that localized HIF-1 inhibition, using a dominant-negative HIF-1 alpha adenoviral construct, prevented carotid artery post-injury remodelling in rats.We propose that HIF-1 is centrally involved in carotid artery remodelling in response to arterial injury and that localized inhibition of HIF-1 may be a novel therapeutic strategy to prevent carotid stenosis.