Sodium Nitroprusside Stimulation of Elastic Matrix Regeneration by Aneurysmal Smooth Muscle Cells
Sodium Nitroprusside Stimulation of Elastic Matrix Regeneration by Aneurysmal Smooth Muscle Cells
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DOI：
10.1089/ten.tea.2022.0169
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发表时间：
2023-02-27
影响因子：
4.1
通讯作者：
Ramamurthi，Anand
中科院分区：
文献类型：
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作者：
Bastola，Suraj;Kothapalli，Chandrasekhar;Ramamurthi，Anand
基质金属蛋白酶的慢性过表达导致弹性基质的降解和丢失，导致组织弹性的降低，这是蛋白水解性疾病的病理生理学的核心，例如腹主动脉瘤(AAAs)，这是局限性的容易破裂的主动脉扩张。影响组织修复以缓解这种情况取决于恢复主动脉壁弹性基质的动态平衡。这自然是不可逆的，因为成体和患病的血管细胞弹性较差，组装成熟弹性纤维的能力受损，尤其是由于AAA壁组织中一氧化氮(NO)信号的丢失而导致的内侧平滑肌细胞(SMCs)表型变化。在这项研究中，我们报道了原代人动脉瘤样平滑肌细胞(AHASMCs)暴露于NO供体药物硝普钠(SNP)在改善细胞外基质动态平衡，特别是弹性纤维组装和抑制蛋白降解方面的好处。硝普钠(100 nM)在基因水平(p<； )和蛋白水平(p<； )均上调弹性基质再生，但不影响细胞增殖，促进交联酶赖氨酰氧化酶(p<； )基因和蛋白表达(p<； 0.05)，显著抑制基质金属蛋白酶2(MMP2)的表达(p<；MMP0.05)，促进收缩的SMC表型。此外，SNP还减弱了在AAA形成和进展中起重要作用的丝裂原激活蛋白激酶的表达。我们的结果表明，SNP有望在治疗中增强弹性基质再生，并具有修复AAA壁的前景。影响陈述慢性和自然不可逆酶降解和弹性纤维的丢失是腹主动脉瘤(AAA)等蛋白水解性疾病的中心。这与成年和患病血管细胞的弹性较差有关，从而影响了它们组装成熟弹性纤维的能力。为了解决这一问题，我们展示了一氧化氮供体药物硝普钠对动脉瘤性平滑肌细胞的表型调节特性，以及它在恢复弹性基质动态平衡方面的剂量特异性促弹力生成和抗蛋白分解特性。结合局部、受控给药载体的发展，这可能导致未来AAA壁修补术的一种新的非手术方法。
The chronic overexpression of matrix metalloproteases leading to consequent degradation and loss of the elastic matrix with the reduction in tissue elasticity is central to the pathophysiology of proteolytic disorders, such as abdominal aortic aneurysms (AAAs), which are localized rupture-prone aortic expansions. Effecting tissue repair to alleviate this condition is contingent on restoring elastic matrix homeostasis in the aortic wall. This is naturally irreversible due to the poor elastogenicity of adult and diseased vascular cells, and the impaired ability to assemble mature elastic fibers, more so in the context of phenotypic changes to medial smooth muscle cells (SMCs) owing to the loss of nitric oxide (NO) signaling in the AAA wall tissue. In this study, we report the benefits of the exposure of primary human aneurysmal SMCs (aHASMCs) to NO donor drug, sodium nitroprusside (SNP), in improving extracellular matrix homeostasis, particularly aspects of elastic fiber assembly, and inhibition of proteolytic degradation. SNP treatment (100 nM) upregulated elastic matrix regeneration at both gene (p< 0.05) and protein levels (p< 0.01) without affecting cell proliferation, improved gene, and protein expression of crosslinking enzyme, lysyl oxidase (p< 0.05), inhibited the expression of MMP2 (matrix metalloprotease 2) significantly (p< 0.05) and promoted contractile SMC phenotypes in aHASMC culture. In addition, SNP also attenuated the expression of mitogen-activated protein kinases, a significant player in AAA formation and progression. Our results indicate the promise of SNP for therapeutic augmentation of elastic matrix regeneration, with prospects for wall repair in AAAs.Impact StatementChronic and naturally irreversible enzymatic degradation and loss of elastic fibers are centric to proteolytic disorders such as abdominal aortic aneurysms (AAAs). This is linked to poor elastogenicity of adult and diseased vascular cells, compromising their ability to assemble mature elastic fibers. Toward addressing this, we demonstrate the phenotype-modulatory properties of a nitric oxide donor drug, sodium nitroprusside on aneurysmal smooth muscle cells, and its dose-specific proelastogenic and antiproteolytic properties for restoring elastic matrix homeostasis. Combined with the development of vehicles for site-localized, controlled drug delivery, this can potentially lead to a new nonsurgical approach for AAA wall repair in the future.