载脂蛋白(a)反义治疗后脂蛋白(a)显著降低，可减少脂蛋白(a)升高患者循环单核细胞的促炎激活。
Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).
作者信息
Stiekema Lotte C A, Prange Koen H M, Hoogeveen Renate M, Verweij Simone L, Kroon Jeffrey, Schnitzler Johan G, Dzobo Kim E, Cupido Arjen J, Tsimikas Sotirios, Stroes Erik S G, de Winther Menno P J, Bahjat Mahnoush
机构信息
Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
出版信息
Eur Heart J. 2020 Jun 21;41(24):2262-2271. doi: 10.1093/eurheartj/ehaa171.
AIMS
Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a).
METHODS AND RESULTS
Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C).
CONCLUSION
Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).
目的
脂蛋白(a)[Lp(a)]升高与心血管疾病(CVD)风险增加密切相关。我们之前报道，循环单核细胞的促炎激活是Lp(a)介导CVD的一种潜在机制。由于强效降低Lp(a)的疗法不断涌现，因此Lp(a)升高的患者在Lp(a)大幅降低后是否会产生有益的抗炎作用备受关注。
方法与结果
通过转录组分析，我们发现Lp(a)升高的健康个体以及Lp(a)水平升高的CVD患者的循环单核细胞均具有促炎基因表达谱。在两项局部亚研究中探讨了降低Lp(a)对单核细胞基因表达和功能的影响，其中一项研究纳入了14例Lp(a)升高的CVD患者，他们接受了载脂蛋白(a)[apo(a)]反义药物(AKCEA-APO(a)-LRx)(NCT03070782)治疗，另一项研究纳入了18例Lp(a)升高的患者，他们接受了前蛋白转化酶枯草溶菌素/kexin 9型抗体(PCSK9ab)治疗(NCT02729025)。AKCEA-APO(a)-LRx使Lp(a)降低了47%，并降低了Lp(a)升高的CVD患者单核细胞中的促炎基因表达，这与体外单核细胞跨内皮迁移能力的功能降低相一致(-17%，P<0.001)。相比之下，PCSK9ab治疗使Lp(a)降低了16%，尽管低密度脂蛋白胆固醇(LDL-C)额外降低了65%，但并未改变单核细胞的转录组和功能特性。
结论
AKCEA-APO(a)-LRx强效降低Lp(a)，而非PCSK9ab治疗适度降低Lp(a)并联合降低LDL-C，降低了Lp(a)升高患者循环单核细胞的促炎状态。这些体外数据支持大幅降低Lp(a)对Lp(a)升高患者具有有益作用。
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