Salyers 2022 JVS Vasc Sci
|Salyers ZR, Mariani V, Balestrieri N, Kumar RA, Vugman NA, Thome T, Villani KR, Berceli SA, Scali ST, Vasilakos G, Ryan TE (2022) S100A8 and S100A9 are elevated in chronically threatened ischemic limb muscle and induce ischemic mitochondrial pathology in mice. https://doi.org/10.1016/j.jvssci.2022.03.003|
» JVS Vasc Sci 3:232-45. PMID: 35647565 Open Access
Salyers Zachary R, Mariani Vinicius, Balestrieri Nicholas, Kumar Ravi A, Vugman Nicholas A, Thome Trace, Villani Katelyn R, Berceli Scott A, Scali Salvatore T, Vasilakos Georgios, Ryan Terence E (2022) JVS Vasc Sci
Abstract: The objective of the present study was to determine whether elevated levels of S100A8 and S100A9 (S100A8/A9) alarmins contribute to ischemic limb pathology.
Gastrocnemius muscle was collected from control patients without peripheral arterial disease (PAD; n = 14) and patients with chronic limb threatening limb ischemia (CLTI; n = 14). Mitochondrial function was assessed in permeabilized muscle fibers, and RNA and protein analyses were used to quantify the S100A8/A9 levels. Additionally, a mouse model of hindlimb ischemia with and without exogenous delivery of S100A8/A9 was used.
Compared with the non-PAD control muscles, CLTI muscles displayed significant increases in the abundance of S100A8 and S100A9 at both mRNA and protein levels (P < .01). The CLTI muscles also displayed significant impairment in mitochondrial oxidative phosphorylation and increased mitochondrial hydrogen peroxide production compared with the non-PAD controls. The S100A8/A9 levels correlated significantly with the degree of muscle mitochondrial dysfunction (P < .05 for all). C57BL6J mice treated with recombinant S100A8/A9 displayed impaired perfusion recovery and muscle mitochondrial impairment compared with the placebo-treated mice after hindlimb ischemia surgery. These mitochondrial deficits observed after S100A8/A9 treatment were confirmed in the muscle cell culture system under normoxic conditions.
The S100A8/A9 levels were increased in CLTI limb muscle specimens compared with the non-PAD control muscle specimens, and the level of accumulation was associated with muscle mitochondrial impairment. Elevated S100A8/A9 levels in mice subjected to hindlimb ischemia impaired perfusion recovery and mitochondrial function. Together, these findings suggest that the inflammatory mediators S100A8/A9 might be directly involved in ischemic limb pathology. • Keywords: Inflammation, Mitochondria, Peripheral artery disease, Vascular disease • Bioblast editor: Plangger M • O2k-Network Lab: US FL Gainesville Ryan TE
Labels: MiParea: Respiration, Patients Pathology: Cardiovascular
Organism: Human, Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue, Isolated mitochondria
Regulation: PCr;Cr Coupling state: LEAK Pathway: F, N HRR: Oxygraph-2k, O2k-Fluorometer