PKR Inhibition Slows Vascular Aging in Mice
Endothelial dysfunction in blood vessel walls is thought to precede many of the other issues of vascular aging, promoting the development of atherosclerosis and loss of regulation of contraction and dilation of blood vessels. Researchers here investigate the degree to which inflammatory signaling and cellular senescence in the context of endothelial aging may be regulated by one specific signaling pathway.
Protein kinase R (PKR) plays an important role in regulating various signal pathways of innate immune diseases. In the past, it was considered that PKR could only be activated by infectious agents, toll-like receptor ligands, cytokines, and other inherent immune-related factors, to regulate the activation of immune signal pathways and release of immune inflammatory factors. In our recent studies, PKR has been revealed to be a key target in promoting endothelial cell senescence and pulmonary hypertension mediated endothelial injury.
In normal physiological conditions, the endothelium is a crucial regulator of vascular physiology and produces several substances to protect the layer of arteries. However, injured endothelial cells become the initial contributor to promote the development of cardiovascular diseases in a pathological phenotype. We previously reported that PKR triggered IL-1β and HMGB1 release to induce PH development, although how endothelial PKR promotes IL-1β and HMGB1 release in vascular aging still need to be further investigated.
We try to in-depth evaluate whether PKR mediated inflammatory factors release is because of mediating endothelial cell hyperactivation. Despite this, how endothelial PKR-mediated inflammatory factors release induces vascular smooth muscle cells (VSMCs) senescence is still unknown. As the main cell type within the vasculature, VSMCs are responsible for maintaining vascular homeostasis. It can present as contraction phenotype and secretory phenotype.
The phenotype transforming of VSMCs from contraction phenotype to secretory phenotype is a remarkable symbol of vascular aging. In normal blood vessel, contraction phenotype VSMCs is the vast majority type of VSMCs. During the aging process, VSMCs gradually lose the contractile phenotype and acquire the proliferative and secretory phenotype, which eventually contributes to vascular degeneration and vascular remodeling via abnormal self-proliferation and promotes the vascular stiffness by the excessive deposition of collagen and decrease of elastin. Therefore, we hypothesize that endothelial PKR-mediated inflammatory factors release can induce the phenotype transforming of VSMCs to induce vascular aging.
Global knockout of PKR exhibits significantly delayed vascular aging compared to wild-type mice at the same age. In vitro, using PKR siRNA or the cell hyperactivation inhibitor glycine or disulfiram can effectively inhibit H2O2 or palmitic acid-induced endothelial cell hyperactivation, IL-1β and HMGB1 release, and co-cultured VSMC phenotype transforming. These results demonstrate that endothelial PKR activation induces endothelial cell hyperactivation to release HMGB1 and IL-1β, which promotes the phenotype transforming of VSMC and subsequent accelerates the process of vascular aging.