Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.
Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.
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DOI：
10.1186/s12933-024-02133-1
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发表时间：
2024-02-01
影响因子：
9.3
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中科院分区：
文献类型：
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糖尿病是一种危害心血管健康的慢性疾病，常导致继发性微血管并发症，对全球健康具有巨大影响。迫切需要可应用于多个血管床的治疗干预。糖尿病视网膜病变（DR）和糖尿病肾病（DKD）的特征在于早期微血管通透性变化，如果不治疗，分别导致视力损害和肾衰竭。硫酸乙酰肝素裂解酶，乙酰肝素酶，以前已被证明有助于糖尿病微血管并发症，但尚未确定的共同的潜在机制，导致微血管功能障碍的条件，如DR和DKD。在该研究中，使用两种硫酸乙酰肝素消耗的小鼠模型（酶促去除和通过内皮特异性外泌糖蛋白-1敲低的遗传消融）来研究内皮细胞表面（即，内皮糖萼）硫酸乙酰肝素对微血管屏障功能的损失。用荧光显微镜或透射电子显微镜测量内皮糖萼的变化。为了测量对屏障功能的影响，我们在眼睛中使用荧光素钠血管造影术，在肾脏中使用肾小球白蛋白渗透性测定。使用2型糖尿病（T2 D，db/db）小鼠模型来确定使用新型乙酰肝素酶抑制剂OVZ/HS-1638治疗来预防硫酸乙酰肝素损伤的治疗潜力。如上所述测量内皮糖萼变化，并通过眼睛中的白蛋白外渗和肾脏中的肾小球渗透性测定来评估微血管屏障功能。在硫酸乙酰肝素耗尽的两种模型中，内皮糖萼深度减少，视网膜溶质通量和肾小球白蛋白渗透性增加。与媒介物处理的T2 D小鼠相比，用OVZ/HS-1638处理的T2 D小鼠具有改善的内皮糖萼测量值，并且同时保护免于与DR和DKD相关的微血管通透性变化。我们证明了内皮糖萼硫酸乙酰肝素在眼睛和肾脏的微血管屏障功能中起着共同的机制作用。使用新型乙酰肝素酶抑制剂OVZ/HS-1638保护糖尿病中的内皮糖萼损伤，有效地防止了与DR和DKD相关的微血管通透性变化，证明了解决糖尿病微血管并发症的新型全身方法。在线版本包含补充材料，可通过10.1186/s12933-024-02133-1获得。
Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined. In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney. In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD. We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications. The online version contains supplementary material available at 10.1186/s12933-024-02133-1.
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影响因子：
4.2
作者：
Everett LA;Paulus YM
通讯作者：
Paulus YM
醛固酮通过基质金属蛋白酶依赖性糖蛋白糖脂诱导蛋白尿。
影响因子：
19.6
作者：
Butler MJ;Ramnath R;Kadoya H;Desposito D;Riquier-Brison A;Ferguson JK;Onions KL;Ogier AS;ElHegni H;Coward RJ;Welsh GI;Foster RR;Peti-Peterdi J;Satchell SC
通讯作者：
Satchell SC
影响因子：
6.5
作者：
Bernard, D;Méhul, B;Schmidt, R
通讯作者：
Schmidt, R
影响因子：
4.6
作者：
Hanna, Ramy M.;Lopez, Eduardo A.;Gorin, Michael B.
通讯作者：
Gorin, Michael B.
影响因子：
19.6
作者：
Desideri S;Onions KL;Qiu Y;Ramnath RD;Butler MJ;Neal CR;King MLR;Salmon AE;Saleem MA;Welsh GI;Michel CC;Satchell SC;Salmon AHJ;Foster RR
通讯作者：
Foster RR