Improving smooth muscle cell exposure to drugs from drug-eluting stents at early time points: a variable compression approach

2013 ◽  
Vol 13 (4) ◽  
pp. 771-781
Author(s):  
Barry M. O’Connell ◽  
Eoghan M. Cunnane ◽  
William J. Denny ◽  
Grainne T. Carroll ◽  
Michael T. Walsh
2002 ◽  
Vol 103 (4) ◽  
pp. 347-353 ◽  
Author(s):  
Neil SWANSON ◽  
Qamar JAVED ◽  
Kai HOGREFE ◽  
Anthony GERSHLICK

Local drug delivery by coronary stents is of current research interest. Organ culture of human vascular tissue is a model of intimal hyperplasia. We report an ex vivo organ culture model of stented vessels. This allows stent–artery interactions to be studied in living tissue. The recognized anti-restenosis agent paclitaxel was chosen to test the organ culture model. Mammary artery specimens were cultured ‘closed’ (i.e. without opening them flat) for 72h. Phosphocholine-coated stents, half of them loaded with the anti-restenosis drug paclitaxel, were implanted. The absorption and elution characteristics of paclitaxel were established. Artery tissue remained viable at 72h when cultured closed, despite stent implantation. Specimens developed smooth muscle cell proliferation. The stents absorbed up to 127±29μg of paclitaxel, with a biphasic elution curve. A mean of 13% of the absorbed paclitaxel remained after a 24h perfusion. In mammary artery, these paclitaxel stents reduced or abolished smooth muscle cell proliferation compared with controls. This model allows the effects of stenting on human arterial tissue to be studied for at least 72h, long enough to demonstrate effects on smooth muscle cell proliferation. Phosphocholine-coated stents absorb adequate doses of paclitaxel, which is eluted gradually, inhibiting muscle cell proliferation. Such an organ culture model of stented mammary artery will provide useful data in addition to that from animal or cell culture models of drug-eluting stents.


2019 ◽  
Vol 317 (3) ◽  
pp. H541-H551 ◽  
Author(s):  
Chen Huang ◽  
Wenwen Zhang ◽  
Yuelin Zhu

Vascular smooth muscle cell (SMC) phenotypic modulation contributes to the development of restenosis. A sorafenib-eluting stent was specifically designed to target SMC phenotypic modulation to inhibit in-stent restenosis in the present study. SMC contractile protein from the freshly isolated rat aorta was expressed at a high level, but its expression was dramatically reduced after SMCs were cultured in 10% FBS for 1 wk. After sorafenib treatment, SMC contractile protein expression was markedly upregulated. We further observed that Yes-associated protein (YAP) expression was attenuated after sorafenib treatment in a dose-dependent manner. Overexpression of YAP by lentivirus reversed the expression of sorafenib-induced SMC contractile protein and increased the expression of cyclin D. Mechanistically, sorafenib regulated the serum response factor-myocardin (SRF-Myocd) complex through competitive binding of YAP to Myocd and increased SRF binding to CArG-containing regions of SMC-specific contractile genes within intact chromatin, thereby controlling the activity of smooth muscle-specific gene transcription. In a rabbit carotid model, the sorafenib-eluting stent (SFES) dramatically inhibited in-stent restenosis and upregulated SMC contractile protein expression. Overexpression of YAP blocked the antirestenosis effect of SFES and repressed contractile smooth muscle-specific genes in vivo, indicating that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. We demonstrated that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. Targeting SMC phenotypic modulation by drug-eluting stent represents an attractive therapeutic approach for the treatment of occlusive vascular diseases. NEW & NOTEWORTHY In the present study, we demonstrated that sorafenib regulates smooth muscle cell (SMC) phenotypic modulation from a proliferative to a contractile state. Sorafenib induced a myocardin-serum response factor interaction and increased SMC contractile gene transcription through the Yes-associated protein pathway. Moreover, local delivery of sorafenib regulating SMC phenotypic modulation represents a promising strategy in the design of drug-eluting stents.


2004 ◽  
Vol 171 (4S) ◽  
pp. 376-377
Author(s):  
Yongmu Zheng ◽  
Shaohua Chang ◽  
Alan J. Wein ◽  
Samuel Chacko ◽  
Michael E. DiSanto

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