Terwilliger 2021 Vasc Med
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 (2021) Racial differences in the limb skeletal muscle transcriptional programs of patients with critical limb ischemia. Vasc Med 26:247-58. |
Terwilliger Zoe S, Ryan Terence E, Goldberg Emma J, Schmidt Cameron A, Yamaguchi Dean J, Karnekar Reema, Brophy Patricia, Green Thomas D, Zeczycki Tonya N, Gabhan Feilim Mac, Annex Brian H, McClung Joseph M (2021) Vasc Med
Abstract: 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. β’ Keywords: Critical limb ischemia (CLI), Genetics, Health disparities, Ischemia, Mitochondria, Peripheral artery disease (PAD), Skeletal muscle β’ Bioblast editor: Reiswig R β’ O2k-Network Lab: US FL Gainesville Ryan TE
Labels: MiParea: Respiration, Patients
Pathology: Cardiovascular
Organism: Human Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase
Coupling state: LEAK, OXPHOS Pathway: N, S, CIV, NS, ROX HRR: Oxygraph-2k
2021-07