Rapamycin promoted thrombosis and platelet adhesion to endothelial cells by inducing membrane remodeling

BMC Cell Biology

Jian-Ping Cai⁵  Chen Wang²  Jian Li⁵  Jin Liu⁶  Jian-Xin Pang⁴  Dong-Ge Liu⁴  Ya-Li Ren¹  Jun Luo⁵  Yong Lan³  Ping Jiang⁵ 

[1] Laboratory of Electron Microscopy, Peking University First Hospital, Beijing 100034, China;Department of Respiratory Medicine, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China;Department of Vascular Surgery, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China;Department of Pathology, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China;The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, No.1, DaHua Road, Dong Dan, Beijing 100730, P.R.China;College of Lifesciences, Beijing Normal University, Beijing 100875, China

关键词: Platelet;    Endothelial cell;    Membrane remodeling;    Thrombosis;   

Others  :  854710
DOI  :  10.1186/1471-2121-15-7

 received in 2013-03-22, accepted in 2014-02-06,  发布年份 2014

【 摘 要 】

Background

Recently, evidence indicated that the rapamycin-eluting stent which was used worldwide may contribute to an increased risk for thrombosis. On the contrary, other researchers found it was safe. Thus, it is necessary to clarify the effect of rapamycin on thrombosis and the corresponding mechanisms.

Results

The effects of rapamycin in vivo were evaluated by modified deep vein thrombosis animal model. The platelets were from healthy volunteers and the platelet-endothelium (purchased from ATCC) adhesion in cultured endothelial cells was assessed. Membrane rufflings in endothelial cells were examined by confocal and electron microscope. Thrombus formation increased in rats that were injected with rapamycin. Electron microscope analysis exhibited microvilli on the rapamycin-treated endothelium in rats. Rapamycin enhanced membrane ruffling in human umbilical vein endothelial cells (HUVECs) and adhesion of platelets to HUVECs. The platelet-HUVECs adhesion was attenuated when cells were treated with cytochalacin B. Inhibition of autophagy by 3-methyladenine led to suppression of membrane ruffles in HUVECs and augmentation of platelet-endothelial adhesion.

Conclusions

In conclusion, we found that endothelial membrane remodeling induced by rapamycin is crucial for the adhesion of platelets to endothelial cells and thereby for thrombosis in vivo, and that the endothelial membrane remodeling is autophagy dependent.

【 授权许可】

   
2014 Jiang et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Goldhaber SZ, Bounameaux H: Pulmonary embolism and deep vein thrombosis. Lancet 2012, 379:1835-1846.
• [2]Nishimura S, Manabe I, Nagasaki M, Kakuta S, Iwakura Y, Takayama N, Ooehara J, Otsu M, Kamiya A, Petrich BG, Urano T, Kadono T, Sato S, Aiba A, Yamashita H, Sugiura S, Kadowaki T, Nakauchi H, Eto K, Nagai R: In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling. Blood 2012, 119:e45-e56.
• [3]Barr J, Chauhan AK, Schaeffer GV, Hansen JK, Motto DG: Red blood cells mediate the onset of thrombosis in the ferric chloride murine model. Blood 2013, 121:3733-3741.
• [4]Wang Y, Andrews M, Yang Y, Lang S, Jin JW, Cameron-Vendrig A, Zhu G, Reheman A, Ni H: Platelets in thrombosis and hemostasis: old topic with new mechanisms. Cardiovasc Hematol Disord Drug 2012, 12:126-132.
• [5]Tsunoda N, Kokubo K, Sakai K, Fukuda M, Miyazaki M, Hiyoshi T: Surface roughness of cellulose hollow fiber dialysis membranes and platelet adhesion. ASAIO J 1999, 45:418-423.
• [6]Herman IM, Brant AM, Warty VS, Bonaccorso J, Klein EC, Kormos RL, Borovetz HS: Hemodynamics and the vascular endothelial cytoskeleton. J Cell Biol 1987, 105:291-302.
• [7]Kublickiene K, Fu XD, Svedas E, Landgren BM, Genazzani AR, Simoncini T: Effects in postmenopausal women of estradiol and medroxyprogesterone alone and combined on resistance artery function and endothelial morphology and movement. J Clin Endocrinol Metab 2008, 93:1874-1883.
• [8]Kadandale P, Stender JD, Glass CK, Kiger AA: Conserved role for autophagy in Rho1-mediated cortical remodeling and blood cell recruitment. Proc Natl Acad Sci USA 2010, 107:10502-10507.
• [9]Barilli A, Visigalli R, Sala R, Gazzola GC, Parolari A, Tremoli E, Bonomini S, Simon A, Closs EI, Dall'Asta V, Bussolati O: In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function. Cardiovasc Res 2008, 78:563-571.
• [10]Camici GG, Steffel J, Amanovic I, Breitenstein A, Baldinger J, Keller S, Lüscher TF, Tanner FC: Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents. Eur Heart J 2010, 31:236-242.
• [11]Ma Q, Zhou Y, Nie X, et al.: Rapamycin affects tissue plasminogen activator and plasminogen activator inhibitor 1 expression: a potential prothrombotic mechanism of drug-eluting stents. Angiology 2012, 63:330-335.
• [12]Daemen J, Kukreja NN, van Twisk PH, Onuma Y, de Jaegere PP, van Domburg R, Serruys PW: Four-year clinical follow-up of the rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital registry. Am J Cardiol 2008, 101:1105-1111.
• [13]Qian J, Xu B, Lansky AJ, Yang YJ, Qiao SB, Wu YJ, Chen J, Hu FH, Yang WX, Mintz GS, Leon MB, Gao RL: First report of a novel abluminal groove filled biodegradable polymer rapamycin-eluting stent in de novo coronary artery disease: results of the first in man FIREHAWK trial. Chin Med J (Engl) 2012, 125:970-976.
• [14]Iba T, Aihara K, Kawasaki S, Yanagawa Y, Niwa K, Ohsaka A: Formation of the venous thrombus after venous occlusion in the experimental mouse model of metabolic syndrome. Thromb Res 2012, 129:e246-e250.
• [15]Stroka KM, Aranda-Espinoza H: Effects of morphology vs. cell-cell interactions on endothelial cell stiffness. Cell Mol Bioeng 2011, 4:9-27.
• [16]Mizushima N, Yoshimori T, Levine B: Methods in mammalian autophagy research. Cell 2010, 140:313-326.
• [17]Egan K, Crowley D, Smyth P, O'Toole S, Spillane C, Martin C, Gallagher M, Canney A, Norris L, Conlon N, McEvoy L, Ffrench B, Stordal B, Keegan H, Finn S, McEneaney V, Laios A, Ducrée J, Dunne E, Smith L, Berndt M, Sheils O, Kenny D, O'Leary J: Platelet adhesion and degranulation induce pro-survival and pro-angiogenic signalling in ovarian cancer cells. PLoS One 2011, 6:e26125.
• [18]Henke PK, Wakefield TW, Kadell AM, Linn MJ, Varma MR, Sarkar M, Hawley A, Fowlkes JB, Strieter RM: Interleukin-8 administration enhances venous thrombosis resolution in a rat model. J Surg Res 2011, 99:84-91.
• [19]Schmidtke DW, Diamond SL: Direct observation of membrane tethers formed during neutrophil attachment to platelets or P-selectin under physiological flow. J Cell Biol 2000, 149:719-730.
• [20]Akbar H, Shang X, Perveen R, Berryman M, Funk K, Johnson JF, Tandon NN, Zheng Y: Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation. PLoS One 2011, 6:e22117.
• [21]Maxwell MJ, Westein E, Nesbitt WS, Giuliano S, Dopheide SM, Jackson SP: Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation. Blood 2007, 109:566-576.
• [22]Nesbitt WS, Westein E, Tovar-Lopez FJ, Tolouei E, Mitchell A, Fu J, Carberry J, Fouras A, Jackson SP: A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 2009, 15:665-673.
• [23]Carmeliet P, De Smet F, Loges S, Mazzone M: Branching morphogenesis and antiangiogenesis candidates: tip cells lead the way. Nat Rev Clin Oncol 2009, 6:315-326.
• [24]Guezguez B, Vigneron P, Lamerant N, Kieda C, Jaffredo T, Dunon D: Dual role of melanoma cell adhesion molecule (MCAM)/CD146 in lymphocyte endothelium interaction: MCAM/CD146 promotes rolling via microvilli induction in lymphocyte and is an endothelial adhesion receptor. J Immunol 2007, 179:6673-6685.
• [25]Sadoshima J: The role of autophagy during ischemia/reperfusion. Autophagy 2008, 4:402-403.
• [26]Codogno P, Mehrpour M, Proikas-Cezanne T: Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol 2011, 13:7-12.
• [27]Hayashi S, Yamamoto A, You F, Yamashita K, Ikegame Y, Tawada M, Yoshimori T, Shimizu S, Nakashima S: The stent-eluting drugs sirolimus and paclitaxel suppress healing of the endothelium by induction of autophagy. Am J Pathol 2009, 175:2226-2234.
• [28]Zhaorigetu S, Yang Z, Toma I, McCaffrey TA, Hu CA: Apolipoprotein L6, induced in atherosclerotic lesions, promotes apoptosis and blocks Beclin 1-dependent autophagy in atherosclerotic cells. J Biol Chem 2011, 286:27389-27398.