Inflammatory cGAS-STING Signaling in Age-Related Endothelial Dysfunction

Chronic, unresolved inflammatory signaling is a feature of aging, the result of lingering senescent cells, debris from stressed cells, and other processes. When persistent over time, inflammatory signaling is highly disruptive to cell and tissue function, altering behavior in ways that contribute to a wide variety of pathologies. In the vasculature, this includes atherosclerosis, calcification, loss of compliance in the vascular smooth muscle responsible for contraction and dilation of blood vessels, and a range of more subtle problems, lumped under the heading of endothelial dysfunction, at the inner surface of blood vessels.

Endothelial dysfunction, a leading cause of abnormal vasodilation, is the basis of many cardiovascular diseases. Improving endothelial function has been shown to be beneficial in the prevention and treatment of hypertension and coronary heart disease (CHD). However, to date, little is known about the effects of existing methods on the prevention of endothelial dysfunction. Therefore, exploring the mechanism of endothelial dysfunction may be beneficial in the development of more effective therapeutic targets. Endothelial nitric oxide synthase (eNOS) is a vital enzyme required for NO synthesis in endothelial cells and is the primary regulator of homeostasis and vascular tone. A decline in eNOS expression often leads to increased vascular tension and decreased local blood perfusion, which are responsible for the development of many cardiovascular diseases.

Sterile inflammation has been shown to occur with aging. This type of inflammatory response is due to immune dysfunction and is closely associated with aging-related organ dysfunction. Evidence suggests that the increase in pro-inflammatory factors caused by sterile inflammation reduces vascular eNOS expression and NO production, leading to vasodilation dysfunction and ultimately aging-related cardiovascular diseases. However, the mechanisms involved in the regulation of age-related aseptic inflammation need further exploration.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a newly discovered component of the innate immune system. The cGAS acts as a cytoplasmic DNA sensor, and its activation leads to activation of the downstream target STING, and subsequent phosphorylation of interferon regulatory factor 3 (IRF3). The main targets of IRF3 are inflammatory genes such as interferon-β (IFNβ), Ifit1, Ifit2, Ifit3, and MCP-1. Increased transcription of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and IL-6 eventually lead to sterile inflammation. Sterile inflammation is similar to inflammation that appears during infection and may be responsible for tissue injury.

A decline in endothelial function, up-regulation of p53, p21, and p16 expression, and activation of the cGAS-STING pathway were observed in aging mice. Inhibition of cGAS was found to improve endothelial function and reverse the increased expression of aging markers. Our in vitro data demonstrated that D-galactose induced a decrease in eNOS expression and cell senescence, which could be partly reversed by cGAS inhibitor, STING inhibitor, siRNA-cGAS and siRNA-STING treatment. Higher expression levels of cGAS, STING, and p-IRF3 were observed in aged human aortic intima tissue compared to young aortic intima tissue. Our study demonstrated that activation of the cGAS-STING pathway played a vital role in aging-related endothelial dysfunction. Thus, the cGAS-STING pathway may be a potential target for the prevention of cardiovascular diseases in the elderly.