Racial differences in the limb skeletal muscle transcriptional programs of patients with critical limb ischemia.
Racial differences in the limb skeletal muscle transcriptional programs of patients with critical limb ischemia.
复制标题
严重肢体缺血患者肢体骨骼肌转录程序的种族差异。
DOI：
10.1177/1358863x20983918
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
McClung JM
中科院分区：
文献类型：
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作者：
Terwilliger ZS;Ryan TE;Goldberg EJ;Schmidt CA;Yamaguchi DJ;Karnekar R;Brophy P;Green TD;Zeczycki TN;Mac Gabhann F;Annex BH;McClung JM
严重肢体缺血(CLI)是外周动脉疾病(PAD)最严重的表现，具有高发病率和高死亡率的特点。与大多数严重的心血管疾病表现一样，黑人不成比例地患有CLI。因此，仍然需要更好地了解这种差异的原因，并促进针对这一人群的个性化治疗选择。从白色和黑色健康成人志愿者和CLI患者中获取腓肠肌，进行全转录组鸟枪测序(WTSS)和浓缩分析，以确定特定反应组途径的变化。与种族匹配的健康对照组相比，患有CLI的白人和黑人患者在多种底物上的核和线粒体编码基因以及线粒体耗氧量显示出类似的减少，表明与截肢结果相关的共同生物能量范式与种族无关。对患有CLI的白人和黑人患者的组织进行直接比较，发现黑人患者四肢肌肉的止血、细胞外基质组织、血小板调节和血管壁相互作用发生了独特的变化。在传统的血管生长因子信号转导靶点中，WTSS显示只有Tie1在黑肢肌肉组织中与白色水平有显著差异。定量逆转录聚合酶链式反应对选定的识别靶标的验证验证了WTSS的方向性变化，并支持MMP9的减少和NUDT4P1和GRIK2的增加，这是患有CLI的黑人患者四肢肌肉所特有的。这代表着在更好地理解黑人和白人患者在与CLI相关的截肢设置中转录程序的异同方面迈出的关键的第一步，并为这一人群的治疗开发提供了一个充满希望的开端。
Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and is characterized by high rates of morbidity and mortality. As with most severe cardiovascular disease manifestations, Black individuals disproportionately present with CLI. Accordingly, there remains a clear need to better understand the reasons for this discrepancy and to facilitate personalized therapeutic options specific for this population. Gastrocnemius muscle was obtained from White and Black healthy adult volunteers and patients with CLI for whole transcriptome shotgun sequencing (WTSS) and enrichment analysis was performed to identify alterations in specific Reactome pathways. When compared to their race-matched healthy controls, both White and Black patients with CLI demonstrated similar reductions in nuclear and mitochondrial encoded genes and mitochondrial oxygen consumption across multiple substrates, indicating a common bioenergetic paradigm associated with amputation outcomes regardless of race. Direct comparisons between tissues of White and Black patients with CLI revealed hemostasis, extracellular matrix organization, platelet regulation, and vascular wall interactions to be uniquely altered in limb muscles of Black individuals. Among traditional vascular growth factor signaling targets, WTSS revealed only Tie1 to be significantly altered from White levels in Black limb muscle tissues. Quantitative reverse transcription polymerase chain reaction validation of select identified targets verified WTSS directional changes and supports reductions in MMP9 and increases in NUDT4P1 and GRIK2 as unique to limb muscles of Black patients with CLI. This represents a critical first step in better understanding the transcriptional program similarities and differences between Black and White patients in the setting of amputations related to CLI and provides a promising start for therapeutic development in this population.