目的: 探究柚皮素对马凡综合征胸主动脉瘤的作用。方法: 对马凡综合征模型Fbn1^C1039G/+小鼠进行柚皮素灌胃，观察柚皮素对小鼠胸主动脉瘤形成的影响，并在体外利用生物荧光共振能量转移、原子力显微镜、同位素标记配体-受体结合等技术探究柚皮素发挥作用的分子机制。结果: Fbn1^C1039G/+小鼠予以柚皮素长期预防性给药(6~26周)或治疗性给药(20~26周)均显著抑制小鼠胸主动脉瘤的扩张和弹力板的断裂。同时，柚皮素喂养可降低小鼠血管壁Smad2和细胞外调节蛋白激酶1/2(extracellular regulating kinase 1/2，ERK1/2)的磷酸化以及基质金属蛋白酶(matrix metalloproteinase, MMP)2/9的表达与活性。机制上，柚皮素处理降低血管紧张素Ⅱ(angiotensin Ⅱ，Ang Ⅱ)受体1(angiotensin Ⅱ type 1 receptor，AT1)下游Gq蛋白介导的蛋白激酶C(protein kinase C，PKC)和ERK1/2的磷酸化、钙离子信号和活化T细胞核因子(nuclear factor of activated T-cells, NFAT)信号，同时柚皮素可降低Ang Ⅱ引起的AT1受体内化及β-抑制蛋白-2与AT1受体的结合，并拮抗与AT1的配体-受体结合；柚皮素可以降低转化生长因子-β(transforming growth factor-β，TGF-β)信号通路下游基因的表达，并显著降低Fbn1^C1039G/+小鼠血浆中过高的TGF-β水平。血小板是体内TGF-β的主要储存细胞，而柚皮素处理可以抑制凝血酶引起的血小板激活，减轻Fbn1^C1039G/+小鼠的血小板活化程度，并降低血小板分泌TGF-β的水平。结论: 柚皮素可能通过抑制AT1受体信号及减少TGF-β产生从而抑制马凡综合征胸主动脉瘤的发生与发展。

Objective: To identify whether naringenin plays a protective role during thoracic aneurysm formation in Marfan syndrome. Methods: To validate the effect of naringenin, Fbn1^C1039G/+ mice, the mouse model of Marfan syndrome, were fed with naringenin, and the disease progress was evaluated. The molecular mechanism of naringenin was further investigated via in vitro studies, such as bioluminescence resonance energy transfer (BRET), atomic force microscope and radioligand receptor binding assay. Results: Six-week-old Fbn1^C1039G/+ mice were fed with naringenin for 20 weeks. Compared with the control group, naringenin significantly suppressed the aortic expansion [Fbn1^C1039G/+ vs. Fbn1^C1039G/++naringenin: (2.49±0.47) mm, n=18 vs. (1.87±0.19) mm, n=22, P < 0.05], the degradation of elastin, and the expression and activity of matrix metalloproteinase 2 (MMP2) and MMP9 in the ascending aorta of Fbn1^C1039G/+ mice. Besides, treatment with naringenin for 6 weeks also attenuated the disease progress among the 20-week-old Fbn1^C1039G/+ mice with established thoracic aortic aneurysms [Fbn1^C1039G/+ vs. Fbn1^C1039G/++naringenin: (2.24±0.23) mm, n=8 vs. (1.90±0.17) mm, n=8, P < 0.05]. To understand the underlying molecular mechanisms, we examined the effects of naringenin on angiotensin Ⅱ type 1 receptor (AT1) signaling and transforming growth factor-β (TGF-β) signaling respectively, which were the dominant signaling pathways contributing to aortopathy in Marfan syndrome as previously reported. The results showed that naringenin decreased angiotensin Ⅱ (Ang Ⅱ)-induced phosphorylation of protein kinase C (PKC) and extracellular regulating kinase 1/2 (ERK1/2) in HEK293A cell overexpressing AT1 receptor. Moreover, naringenin inhibited Ang Ⅱ-induced calcium mobilization and uclear factor of activated T-cells (NFAT) signaling. The internalization of AT1 receptor and its binding to β-arrestin-2 with Ang Ⅱ induction were also suppressed by naringenin. As evidenced by atomic force microscope and radioligand receptor binding assay, naringenin inhibited Ang Ⅱ binding to AT1 receptor. In terms of TGF-β signaling, we found that feeding the mice with naringenin decreased the phosphorylation of Smad2 and ERK1/2 as well as the expression of TGF-β downstream genes. Besides, the serum level of TGF-β was also decreased by naringenin in the Fbn1^C1039G/+ mice. Furthermore, we detected the effect of naringenin on platelet, a rich source of TGF-β, both in vivo and in vitro. And we found that naringenin markedly decreased the TGF-β level by inhibiting the activation of platelet. Conclusion: Our study showed that naringenin has a protective effect on thoracic aortic aneurysm formation in Marfan syndrome by suppressing both AT1 and TGF-β signaling.