Levels of calcium-sensor protein, S100A1, are downregulated in patients with critical limb ischemia (CLI), say researchers who believe the protein could be a potential therapeutic target to promote revascularization.
Patrick Most (University of Heidelberg, Germany) and team found that patients with chronic CLI showed almost complete loss of S100A1 expression in hypoxic tissue. Further analysis in S100A1 knockout (SKO) mice that underwent femoral artery resection (FAR) revealed insufficient perfusion recovery and high rates of autoamputation.
Cellular analysis in SKO endothelial cells and human endothelial cells prompted by defective in vivo angiogenesis demonstrated impaired in vitro and in vivo proangiogenic properties, including proliferation, migration, and tube formation. As reported in Circulation Research, it also revealed attenuated vascular endothelial growth factor (VEGF)- and hypoxia-stimulated endothelial nitric oxide synthase (eNOS) activity.
The authors say that in terms of the mechanism, S100A1 deficiency compromised eNOS activity in endothelial cells both by interrupted stimulatory S100A1/eNOS interaction and protein kinase C hyperactivation. This resulted in inhibitory eNOS phosphorylation and enhanced VEGF receptor 2 degradation with attenuated VEGF signaling.
"We have shown a downregulation of S100A1 in patients with CLI and identified the protein as critical for endothelial cell function in ischemic angiogenesis," commented Most in a press statement. "This is a new therapeutic angle."
He added: "Perhaps the most intriguing finding is that S100A1 stimulates directly the source enzyme of nitric oxide in the endothelial cell. Without S100A1, this mechanism is simply blocked and the body's ability to generate new small vessels severely compromised."
Co-author Karsten Peppel (Jefferson Medical College, Philadelphia, USA) says that the team's goal for future research is to determine why levels of the S100A1 protein drop in patients with peripheral arterial occlusive disease, and if restoration of it can improve their condition.
"There is potential with therapeutics, mainly gene therapy, to restore levels and possibly improve revascularization, not only in patients with CLI but also in heart disease due to insufficient blood supply," she said.
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