Role of matrix metalloproteinases and histone deacetylase in oxidative stress-induced degradation of the endothelial glycocalyx
Role of matrix metalloproteinases and histone deacetylase in oxidative stress-induced degradation of the endothelial glycocalyx
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DOI：
10.1152/ajpheart.00090.2018
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发表时间：
2019-03-01
影响因子：
4.8
通讯作者：
Phillips, Shane A.
中科院分区：
文献类型：
--
作者：
Ali, Mohamed M.;Mahmoud, Abeer M.;Phillips, Shane A.
糖萼对正常内皮功能至关重要。它还束缚细胞外超氧化物歧化酶（SOD 3），保护内皮免受氧化损伤。蛋白水解酶[基质金属蛋白酶（MMP）]能够破坏内皮细胞表面蛋白，如多配体聚糖，导致内皮糖萼的紊乱。我们试图测试基质金属蛋白酶在氧化应激介导的内皮糖萼破坏中的作用，并研究基质金属蛋白酶的药理学抑制对减轻这种有害作用的影响。我们还研究了组蛋白去乙酰化酶（HDAC）在氧化应激介导的MMP诱导和糖萼重塑中的作用。氧化应激实验诱导在人类脂肪微血管内皮细胞使用过氧化氢和丁硫氨酸亚砜亚胺在存在和不存在的情况下，有效的MMP和HDAC抑制剂。H2 O2和丁硫酰亚胺导致内皮糖萼的显著损失;它们还增加了MMP-2和MMP-9的表达和蛋白水解活性，随后增加了多配体蛋白聚糖-1和SOD 3从内皮细胞表面的脱落。MMP上调伴随着其抑制剂、金属蛋白酶组织抑制剂（TIMP-1和TIMP-3）的mRNA和蛋白水平的下降。此外，氧化应激诱导HDAC活性。抑制MMPs和HDAC逆转了syndecan-1和SOD 3的脱落，并维持了内皮糖萼的完整性。HDAC抑制增加内皮细胞中TIMP表达并降低MMP表达和活性。我们的研究结果揭示了MMPs和HDAC作为氧化应激诱导的糖萼重塑的治疗靶向机制。新&值得注意的是氧化应激是许多疾病的标志，它会损害内皮糖萼，导致血管功能障碍。研究氧化应激和内皮糖萼紊乱之间的机制联系可能有助于发现新的治疗靶点，以保护血管功能。在这项研究中，我们研究了参与氧化应激诱导的内皮糖萼降解的基质金属蛋白酶和组蛋白脱乙酰酶。
The glycocalyx is crucial for normal endothelial function. It also tethers extracellular superoxide dismutase (SOD3), which protects the endothelium against oxidative damage. Proteolytic enzymes [matrix metalloproteinases (MMPs)] are capable of disrupting endothelial cell surface proteins, such as syndecans, resulting in derangements of the endothelial glycocalyx. We sought to test the role of MMPs in oxidative stress-mediated disruption of the endothelial glycocalyx and examine the effect of pharmacological inhibition of MMPs on mitigating this detrimental effect. We also examined the role of histone deacetylase (HDAC) in the oxidative stress-mediated MMP induction and glycocalyx remodeling. Oxidative stress was experimentally induced in human adipose microvascular endothelial cells using H2O2 and buthionine sulfoximine in the presence and absence of potent MMP and HDAC inhibitors. H2O2 and buthionine sulfoximine resulted in a notable loss of the endothelial glycocalyx; they also increased the expression and proteolytic activity of MMP-2 and MMP-9 and subsequently increased the shedding of syndecan-1 and SOD3 from the endothelial cell surface. MMP upregulation was accompanied by a decline in mRNA and protein levels of their inhibitors, tissue inhibitors of metalloproteinase (TIMPs; TIMP-1 and TIMP-3). Furthermore, oxidative stress induced HDAC activity. Inhibition of MMPs and HDAC reversed syndecan-1 and SOD3 shedding and maintained endothelial glycocalyx integrity. HDAC inhibition increased TIMP expression and reduced MMP expression and activity in endothelial cells. Our findings shed light on MMPs and HDAC as therapeutically targetable mechanisms in oxidative stress-induced glycocalyx remodeling.NEW & NOTEWORTHY Oxidative stress, a hallmark of many diseases, damages the endothelial glycocalyx, resulting in vascular dysfunction. Studying the mechanistic link between oxidative stress and endothelial glycocalyx derangements might help discover new therapeutic targets to preserve vascular function. In this study, we investigated the involvement of matrix metalloproteinases and histone deacetylase in oxidative stress-induced endothelial glycocalyx degradation.