Multifunctional, JNK-inhibiting nanotherapeutics for augmented elastic matrix regenerative repair in aortic aneurysms.
Multifunctional, JNK-inhibiting nanotherapeutics for augmented elastic matrix regenerative repair in aortic aneurysms.
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DOI：
10.1007/s13346-017-0419-y
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发表时间：
2018-08
影响因子：
5.4
通讯作者：
Ramamurthi A
中科院分区：
文献类型：
--
作者：
Camardo A;Seshadri D;Broekelmann T;Mecham R;Ramamurthi A
腹主动脉瘤（AAA）的生长，局部主动脉壁扩张，是由基质金属蛋白酶（MMPs）破坏和随后的主动脉壁弹性纤维损失驱动的。由于弹性纤维不能自然再生或修复，阻止或逆转AAA的生长是不可能的。之前，我们发现强力霉素（DOX），一种MMP抑制剂药物，除了抑制MMPs外，还可以在低μg/ml剂量下刺激弹性基质新组装和交联。我们目前在动脉瘤平滑肌细胞（SMC）培养中发现，外源性DOX在该剂量范围内的作用与其通过抑制调节蛋白c- jun - n末端激酶2 （jnk2）而上调转化生长因子β (TGF-β1)有关。我们已经确定了一个DOX剂量范围，可以刺激弹性发生和交联，而不会对细胞活力产生不利影响。利用jnk2抑制作为DOX促进再生基质效应的指标，我们进一步证明，从聚（乙二醇）-聚（乳酸乙醇酸）纳米颗粒（NPs）中持续、稳定地释放有用剂量的DOX，提供了可能比外源性DOX更明显的促弹性和抗蛋白水解作用。我们将这些结果归因于先前确定的由阳离子两亲基团功能化聚合物NP表面提供的协同效应。释放的DOX抑制JNK的表达和磷酸化，可能会增加TGF-β1的表达，TGF-β1可以增加弹性基质的弹性发生和赖氨酸氧化酶介导的交联。我们的研究结果表明，JNK抑制是评估亲弹性基质再生效果的有用指标，并指出DOX和阳离子功能化NPs提供的组合再生益处。
Growth of abdominal aortic aneurysms (AAA), localized aortal wall expansions, is driven by the disruption and subsequent loss of aortal wall elastic fibers by matrix metalloproteases (MMPs). Since elastic fibers do not naturally regenerate or repair, arresting/reversing AAA growth has not been possible. Previously, we showed utility of doxycycline (DOX), an MMP inhibitor drug, to stimulate elastic matrix neoassembly and crosslinking at low μg/ml doses in addition to inhibiting MMPs. We currently show in aneurysmal smooth muscle cell (SMC) cultures, that effects of exogenous DOX in this dose range are linked to its upregulation of transforming growth factor beta (TGF-β1) via its inhibition of the regulatory protein c-Jun-N-terminal kinase 2 (JNK 2). We have identified a DOX dose range that stimulates elastogenesis and crosslinking without adversely impacting cell viability. Using JNK 2 inhibition as a metric for pro-regenerative matrix effects of DOX, we further demonstrate that sustained, steady state release of DOX at the useful dose, from poly(ethylene glycol)-poly(lactic glycolic acid) nanoparticles (NPs) provides pro-elastogenic and anti-proteolytic effects that could potentially be more pronounced than that of exogenous DOX. We attribute these outcomes to previously determined synergistic effects provided by cationic amphiphile groups functionalizing the polymer NP surface. Released DOX inhibited expression and phosphorylation of JNK to likely increase expression of TGF-β1, which is known to increase elastogenesis and lysyl oxidase-mediated crosslinking of elastic matrix. Our results suggest that JNK inhibition is a useful metric to assess pro-elastic matrix regenerative effects and point to the combinatorial regenerative benefits provided by DOX and cationic-functionalized NPs.
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影响因子：
2.9
作者：
LABARCA, C;PAIGEN, K
通讯作者：
PAIGEN, K
影响因子：
4.8
作者：
Leask, A;Holmes, A;Abraham, DJ
通讯作者：
Abraham, DJ
影响因子：
3.7
作者：
Ahler E;Sullivan WJ;Cass A;Braas D;York AG;Bensinger SJ;Graeber TG;Christofk HR
通讯作者：
Christofk HR
影响因子：
37.8
作者：
Dai, JP;Losy, F;Allaire, E
通讯作者：
Allaire, E
影响因子：
4.3
作者：
Curci, JA;Mao, DL;Thompson, RW
通讯作者：
Thompson, RW