抑制Notch信号对血管紧张素Ⅱ诱导的肺血管重构的影响

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摘要目的：Notch信号对胚胎发育、血管损伤修复、肿瘤生长过程中的血管重构发挥了重要作用，但对肺动脉高压肺血管重构研究很少，本研究旨在探讨抑制Notch信号对血管紧张素Ⅱ（AngII）诱导的肺血管重构的影响。方法：采用AngⅡ持续刺激培养7 d的肺动脉血管条，测定血管管壁厚度及血管壁细胞增殖细胞核抗原（PCNA）和caspase-3阳性率。同时部分血管条还加入γ-分泌酶抑制剂DAPT抑制Notch信号，测定血管条Notch 1~4 受体及其下游转录因子HERP1、HERP2 mRNA水平。结果：AngⅡ持续刺激血管7 d，血管壁厚度增加近50%，伴有血管壁细胞PCNA阳性率升高和caspase-3阳性率降低（P＜0.05）。加入DAPT后，血管条Notch 1~4受体mRNA水平无明显改变，但HERP 1、2 mRNA水平降低（P＜0.05），管壁厚度、PCNA和caspase-3阳性率的改变程度明显降低（P＜0.05）。结论：抑制Notch信号能抑制AngⅡ诱导的肺血管重构，可能成为肺动脉高压治疗的一个新思路。

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	乔莉娜
	许红波
	石坤
	周同甫
	华益民
	刘瀚旻

关键词 ： Notch信号, 血管紧张素, 肺, 血管重构, 大鼠

Abstract：OBJECTIVE: It is known that Notch signal is very important to vascular remodeling during the process of embryonic development, vessel repair and tumor growth, but there are few studies about pulmonary vascular remodeling in pulmonary hypertension. This study was to explore the effect of inhibiting Notch signal on pulmonary vascular remodeling induced by angiotensin Ⅱ. METHODS: Vessel strips taken from healthy Wistar rats were co-cultured with extrogenous angiotensin Ⅱand the potent smooth muscle cell proliferation stimulators for 7 days. Vascular wall thickness, proliferating cell nuclear antigen (PCNA) positive cell rate and caspase-3 positive cell rate were examined in vessel strips. Then some vessel strips were cultured with angiotensin Ⅱ and γ-secretase inhibitor DAPT, a Notch signaling inhibitor for 7 days. The levels of Notch 1 to 4 receptor and HERP1/2 mRNA were ascertained by FQ-PCR. RESULTS: Angiotensin Ⅱstimulation in the cultured normal pulmonary arteries resulted in an increase in the vascular medial thickness by nearly 50%, and a significant increase in the PCNA positive cell rate and a decrease in the caspase-3 positive cell rate. DAPT treatment did not result in the alterations of Notch 1 to 4 receptor levels, but decreased remarkably HERP1 and HERP2 mRNA expression. DAPT treatment also decreased angiotensin Ⅱ-induced vascular medial thickness and PCNA positive cell rate and increased caspase-3 positive cell rate. CONCLUSIONS: Inhibiting Notch signal by γ-secretase inhibitor may lead to the suppression of pulmonary vascular remodeling induced by angiotensin Ⅱ, suggesting that the inhibition of Notch signal pathway might be a novel strategy for the treatment of pulmonary hypertension.

Key words： Notch signal Angiotensin Pulmonary Vascular remodeling Rats

PACS:

R-33

引用本文:

乔莉娜,许红波,石坤等. 抑制Notch信号对血管紧张素Ⅱ诱导的肺血管重构的影响[J]. 中国当代儿科杂志, 2011, 13(6): 503-508.

QIAO Li-Na,XU Hong-Bo,SHI Kun et al. Effect of inhibition of Notch signal on pulmonary vascular remodeling induced by angiotensin Ⅱ[J]. CJCP, 2011, 13(6): 503-508.

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http://www.zgddek.com/CN/ 或 http://www.zgddek.com/CN/Y2011/V13/I6/503

	［1］Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms［J］. Circ Res, 2006, 99(7): 675-691.
	［2］Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension［J］. J Mol Cell Cardiol, 2008, 44(1): 14-30.
	［3］魏丽，刘童，刘斌，王献民，赵亮，周同甫. 雷公藤甲素对实验性肺动脉高压肺脏基质金属蛋白酶MMP2和MMP9的影响［J］. 中国当代儿科杂志, 2007，9(5)：479-483.
	［4］Hofmann JJ, Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what?［J］. Circ Res, 2007, 100(11):1556-1568.
	［5］Ehebauer M, Hayward P, Arias AM. Notch, a universal arbiter of cell fate decision［J］. Science, 2006, 314(5804):1414-1415.
	［6］Morrow D, Guha S, Sweeney C, Birney Y, Walshe T, O′Brien C, et al. Notch and vascular smooth muscle cell phenotype［J］. Cir Res, 2008, 103(12): 1370-1382.
	［7］Kurpinski K, Lam H, Chu J, Wang A, Kim A, Tsay E, et al. Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells［J］. Stem Cell, 2010, 28(4): 734-742.
	［8］Kennard S, Liu H, Lilly B. Transforming growth factor-beta (TGF-1) down-regulates Notch3 in fibroblasts to promote smooth muscle gene expression［J］. J Biol Chem, 2008, 283(3): 1324-1333.
	［9］Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis［J］. Nature, 2007, 445(7129): 776-780.
	［10］Morrow D, Sweeney C, Birney YA, Guha S, Collins N, Cummins PM, et al. Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo［J］. Am J Physiol Cell Physiol, 2007, 292(1): C488-C496.
	［11］王献民，周同甫，刘斌, 魏丽，石坤，赵姗姗，等. 卡托普利及氯沙坦干预大鼠肺动脉高压与MMP-2、MMP-9、TIMP-1表达的关系［J］. 四川大学学报（医学版）, 2009，40(2):255-259.
	［12］王献民，刘斌，魏丽，周同甫，王晓琴，乔丽娜，等.卡托普利及氯沙坦对肺动脉高压大鼠肺组织细胞凋亡的影响［J］.实用儿科临床杂志, 2009, 24(13):999-1003.
	［13］McKie PM, Cataliotti A, Boerrigter G, Chen HH, Sangaralingham SJ, Martin FL, et al. A novel atrial natriuretic peptide based therapeutic in experimental angiotensin II mediated acute hypertension［J］. Hypertension, 2010, 56(6): 1152-1159.
	［14］Bradford CN, Ely DR, Raizada MK. Targeting the vasoprotective axis of the renin-angiotensin system: a novel strategic approach to pulmonary hypertensive therapy［J］. Curr Hypertens Rep, 2010, 12(4): 212-219.
	［15］Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Díez-Freire C, Dooies A, et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension［J］. Am J Respir Crit Care Med, 2010, 182(8): 1065-1072.
	［16］杨栋,谢燕. 西拉普利对缺氧性大鼠肺动脉高压肺血管结构的保护［J］. 中国临床医学, 2008；15(4)：471-473.
	［17］Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, Watanabe N, et al. C-terminal fragment of presenilin is the molecular target of a dipeptidic gamma-secretase-specific inhibition DAPT (N-［N-(3,5-Difluorophenacetyl)-L-alanyl］-S-phenylglycine t-Butyl ester)［J］. J Biol Chem, 2006, 281(21):14670-14676.
	［18］Nelson BR, Hartman BH, Georgi SA, Lan MS, Reh TA. Transient inactivation of Notch signaling synchronizes differentiation of neural progenitor cells［J］. Dev Biol, 2007, 304(2): 479-498.