Article: Inhibition of Protein Kinase C Beta Phosphorylation Activates Nuclear Factor-Kappa B and Improves Postischemic Recovery in Type 1 Diabetes

Authors: Satyanarayana Alleboina, Thomas Wong, Madhu V Singh, Ayotunde O Dokun

Journal: Exp Biol Med (Maywood). 2020 May;245(9):785-796. doi: 10.1177/1535370220920832. Epub 2020 Apr 23.

Abstract:
Peripheral artery disease (PAD) is a major health problem and is caused by atherosclerosis in arteries outside the heart leading to impaired blood flow. The presence of diabetes significantly increases the likelihood of having worse outcomes in PAD, and the molecular mechanisms involved are poorly understood. Hyperglycemia in diabetes activates the nuclear factor-kappa B (NF-κB) pathway, and chronic inflammation in diabetes is associated with vascular complications. Ischemia also activates NF-κB signaling that is important for perfusion recovery in experimental PAD. We hypothesized that prolonged exposure of endothelial cells to high glucose in diabetes impairs ischemic activation of the NF-κB pathway and contributes to poor perfusion recovery in experimental PAD. We assessed the effect of high glucose and ischemia on canonical and non-canonical NF-κB activation in endothelial cells and found both conditions activate both pathways. However, exposure of endothelial cells to high glucose impairs ischemia-induced activation of the canonical NF-κB pathway but not the non-canonical pathway. We probed an array of antibodies against signaling proteins in the NF-κB pathway to identify proteins whose phosphorylation status are altered in endothelial cells exposed to high glucose. Protein kinase C beta (PKCβ) was among the proteins identified, and its role in impaired ischemia-induced activation of NF-κB during hyperglycemia has not been previously described. Inhibition of PKCβ improves ischemia-induced NF-κB activation in vitroand in vivo. It also improves perfusion recovery in diabetic mice following experimental PAD. Thus, in diabetes, PKCβ phosphorylation contributes to impaired ischemic activation of NF-κB and likely a mechanism contributing to poor PAD outcomes.

Link to journal online: https://journals.sagepub.com/doi/full/10.1177/1535370220920832