肽基精氨酸脱氨酶抑制剂通过影响 Akt 信号以及血管生成因子的表达和分泌,降低内皮细胞的血管生成潜能。

IF 2.5 Q3 CELL BIOLOGY Cellular Physiology and Biochemistry Pub Date : 2024-02-19 DOI:10.33594/000000683
Oskar Ciesielski, Luciano Pirola, Aneta Balcerczyk
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引用次数: 0

摘要

背景/目的:内皮细胞(ECs)在各种生理过程中发挥着至关重要的作用,尤其是与心血管系统有关的生理过程,同时也影响着整个机体。内皮细胞的生物学特性受多种生化刺激和基因表达的表观遗传驱动因素的调控。我们从蛋白瓜氨酸化的角度研究了心血管细胞的血管生成潜能,该潜能受肽基精氨酸脱氨酶(PADs)的调控,PADs可修饰组蛋白和非组蛋白。虽然 PADs 参与了多种生理过程、炎症相关疾病和癌症,但它们在血管生成中的作用仍不清楚:为了阐明 PADs 在内皮血管生成中的作用,我们使用了两种人类 EC 模型:原生静脉(HUVECs)和微血管内皮细胞(HMEC-1)。使用不可逆抑制剂抑制了 PADs 的活性:BB-Cl-脒、Cl-脒和 F-脒。我们分析了体外血管生成的所有三个步骤:增殖、迁移和毛细血管样管的形成,以及 ECs 的分泌活动、基因表达和信号传导:结果:所有使用的PAD抑制剂都能减少组蛋白H3瓜氨酸化(H3cit)标记,抑制内皮细胞迁移和毛细血管样管形成,并通过增加PEDF(色素上皮源性因子)和减少VEGF(血管内皮生长因子)mRNA表达和蛋白分泌,促进HMEC-1细胞的血管抑制活性。此外,BB-Cl-脒还能降低 MMPs(基质金属蛋白酶)的总活性。结论:我们的研究结果表明,瓜氨酸化药理抑制剂是一种很有前景的针对血管生成的治疗药物。
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Peptidylarginine Deiminases Inhibitors Decrease Endothelial Cells Angiogenic Potential by Affecting Akt Signaling and the Expression and Secretion of Angiogenic Factors.

Background/aims: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and cancer, their role in angiogenesis remains unclear.

Methods: To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis in vitro : proliferation, migration, and capillary-like tube formation, as well as secretory activities, gene expression and signaling in ECs.

Results: All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>.

Conclusion: Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis.

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来源期刊
CiteScore
5.80
自引率
0.00%
发文量
86
审稿时长
1 months
期刊介绍: Cellular Physiology and Biochemistry is a multidisciplinary scientific forum dedicated to advancing the frontiers of basic cellular research. It addresses scientists from both the physiological and biochemical disciplines as well as related fields such as genetics, molecular biology, pathophysiology, pathobiochemistry and cellular toxicology & pharmacology. Original papers and reviews on the mechanisms of intracellular transmission, cellular metabolism, cell growth, differentiation and death, ion channels and carriers, and the maintenance, regulation and disturbances of cell volume are presented. Appearing monthly under peer review, Cellular Physiology and Biochemistry takes an active role in the concerted international effort to unravel the mechanisms of cellular function.
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