JAHA:“PDE5抑制剂”也有短板!会加速腹主动脉瘤恶化

2022-01-17 郭海君 生物探索

提及“西地那非”或许你会感到陌生,它本是一种研发用于治疗心血管疾病的药物,却意外发现可有效治疗男性勃起功能障碍而广为人知,它就是俗称的“伟哥”(Viagra)。

西地那非于19984月成为美国上市的第一个口服抗阳萎药,使得美国辉瑞公司名声大噪。许多研究已证明:西地那非为磷酸二酯酶(PDEV选择性抑制剂,能在性刺激下增强一氧化氮(NO)释放,从而引起阴茎勃起的生理反应,其中NO是引起海绵体平滑肌松弛和勃起的主要介质。

然而,一些临床病例报道了西地那非的使用与主动脉夹层有关联,并且在人主动脉瘤组织中发现了PDE5A的表达降低。腹主动脉瘤多发于老年男性,尤其是有肺气肿、腹主动脉瘤家族史、高血压、高胆固醇、吸烟以及肥胖人群。近日,在JAHA期刊上发表了题为“Sildenafil Viagra Aggravates the Developmentof Experimental Abdominal Aortic Aneurysm”的研究,揭示了西地那非对腹主动脉瘤恶化的影响。

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研究成果(图源:JAHA

在健康的主动脉壁中,中层由收缩性平滑肌细胞(SMC)和弹性蛋白纤维组成,它们可保持主动脉的粘弹性。而主动脉瘤(AA)是通过内侧SMC的损耗和弹性基质的降解,由渐进壁变性直至造成主动脉的永久扩张,从而最终导致主动脉破裂。

平滑肌收缩主要取决于肌球蛋白轻链(MLC)的磷酸化状态,其受肌球蛋白轻链激酶(MLCK)和肌球蛋白轻链磷酸酶(MLCP)的活性调节。MLCK的激活导致平滑肌收缩,这依赖于Ca2+和钙调蛋白。相反,MLCP激活导致平滑肌松弛。cGMP通过多种不同的机制降低细胞内Ca2+浓度。另外,cGMP通过激活磷酸化MLCP的肌球蛋白结合亚基的cGMP依赖性蛋白激酶 IcGKI,也称为PKGI)增加MLCP活性。因此,cGMP/PKGI 通过促进MLC的去磷酸化来拮抗SMC收缩。

cGMP水解磷酸二酯酶型(PDE5)是cGMP特异性PDE,在血管SMC中高度表达。PDE5通过水解cGMP和拮抗PKGI介导的血管舒张作为SMC收缩的重要调节剂,而西地那非正是PDE5抑制剂之一。

研究团队调查了西地那非对实验性小鼠腹部主动脉瘤(AAA)发展的影响。首先,通过在雄性小鼠中应用主动脉周围弹性蛋白酶结合3-氨基丙腈富马酸盐(BAPN)来阻断弹性蛋白/胶原蛋白交联,手术后7天诱导小鼠产生腹主动脉瘤。然后将这些小鼠随机分为两组,一组每天服用溶解在水中的西地那非,剂量为60-100 mg/kg/天;一组饮用不含西地那非的水。与未服用西地那非的小鼠相比,连续服用4周西地那非的小鼠的腹主动脉瘤更大,平均宽度增加37%;且腹主动脉瘤中弹性纤维的退化或减弱程度增加了50%

接着,研究人员使用免疫荧光染色来检测PDE5A蛋白。与空白对照组相比,AAA内侧病变区域的SMCPDE5A免疫荧光染色强度显着降低。再用SMC标记物对AAA切片进行免疫染色,发现SMC主要定位于中层病变区域(外部弹性层向内的区域)。这些结果表明,PDE5功能的丧失可能与AA的发病机制有关。

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 小鼠AAA组织的中层平滑肌细胞SMC cGMP 水解PDE5A的表达降低(图源:JAHA

研究人员通过对主动脉组织中pMLC和总MLC的免疫染色(经常用作血管SMC收缩的生化指标)来检查西地那非对SMC收缩功能的影响。最后发现,与空白对照组相比,AAA组内侧病变区域的pMLC染色信号显着降低,表明西地那非可以通过抑制MLC磷酸化来降低主动脉SMC收缩性。

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西地那非对AAASMC 2MLC磷酸化的影响(图源:JAHA

 最后,研究人员假设西地那非通过PKGI介导的MLC去磷酸化降低了MLC磷酸化。为了确定西地那非对PKGI的活化作用,通过临近连接测定法(PLA)测定cGMPPKGI的结合。结果显示西地那非治疗AAA组的PLA信号进一步增加,表明西地那非治疗后cGMPPKGI结合增加;而免疫荧光染色显示AAA中的PKGI表达没有被西地那非显着改变。综上,在AAA的主动脉SMC中,西地那非治疗上调了PKG的活化。

图片

西地那非对AAA中层SMCcGMP依赖性PKGI活化的影响(图源:JAHA 

综上所述,西地那非加剧了腹主动脉瘤的恶化。PDE5抑制剂已在临床上用于勃起功能障碍或肺动脉高压的患者,这些患者常有心血管疾病。因此,在使用PDE5抑制剂时,特别是对于易患主动脉或心血管疾病的患者来说可能需要更加谨慎。

参考资料:

[1]Zhang C, Mohan A, Shi H, et al. SildenafilViagraAggravates the Development of Experimental Abdominal Aortic Aneurysm. JAm Heart Assoc. 2022 Jan 5:e023053. doi: 10.1161/JAHA.121.023053. Epub ahead ofprint. PMID: 34984916.

[2]JAHA伟哥被发现可能存在致命副作用,促进腹动脉瘤恶化。http://med.china.com.cn/content/pid/313270/tid/1026

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