Our study disclosed the cardioprotective potential of STING in pressure overload-induced cardiac remodelling, using a realistic model of human heart failure. In detail, STING could participate in cardioprotection from the following aspects:1) reduction of cardiac fibrosis and cardiac hypertrophy; 2) suppression of proinfammatory cytokines production; 3) improvement of cardiac function; 4) inhibition of autophagy; 5) phosphorylation of ULK1.
As a conserved, homeostatic process for the degradation and recycle of intracellular damaged organelles and macromolecules, autophagy has been proved to exert essential roles in improve cardiac function with cardiac remodelling. In fact, the role of autophagy in cardiac hyperthrophy and heart failure is still controversial. Cardiac-specific Atg5 deficiency mice exhibited worse cardiac function and more serious cardiac hypertrophy after pressure overload for 1 week compared with wild type mice. Meanwhile, Atg5 null mice displayed significantly less suppression of left ventricle hypertrophy than the control mice after 7 days, unloading. One clinical research also demonstrated that myofilament alterations and autophagic vacuoles was associated with better prognosis in patients with dilated cardiomyopathy, indicating that autophagy activation may serve as an adaptive response. On the contrary, Beclin-1 overexpression or some pharmacological agonists aggravated cardiac hypertrophy by activating autophagy[6, 24], which implied that excessive autophagy may give cell death and act as an undesirable role in maintain cardiac function. Accumulating evidence unveiled that both excessive and insufficient autophagy could trigger cardiac hypertrophy for the reason that the dynamic balance between cardiac protein degradation and synthesis determines myocardial mass. As for cardiac fibrosis, the maladaptive effect of autophagy is relatively defined. Studies have shown that TGF-β could promote autophagy in human tubular epithelial kidney cells and mouse fibroblasts[25, 26]. In human atrial myofibroblasts, TGF-β may simultaneously trigger autophagy and fibrosis in human atrial myofibroblasts and pharmacological inhibition of autophagy caused the decrease in TGF-β-induced cardiac fibrosis. In our study, autophagy was activated in mice subjected to pressure overload, which was accompanied with deteriorated hypertrophic growth, worse cardiac function, increased fibrosis as well as inflammatory response. However, autophagy inhibition significantly repressed pathological alteration of heart, hinting that autophagy activation may play a negative role in the pathogenesis of chronic heart failure.
STING protein is located on the endoplasmic reticulum, which was firstly discovered in 2008. The original function of STING is to promote type I IFN production upon the stimulation cyclic dinucleotides. In recent years, STING has been recognized as a critical and promising target for various cardiovascular diseases. For instance, STING-IFRF3 axis is critically associated in obesity–induced endothelial injury and inflammation, the inhibition of which could partially protected against adipose tissue inflammation, insulin resistance, obesity, as well as glucose intolerance. In the model of myocardial infarction, suppression of IRF3-dependent signaling leaded to reduced levels of cardiac inflammatory cytokines and decreased inflammatory cell infiltration, apart from relieving left ventricular dilation and improving cardiac function. Our lab previously reported that STING-IRF3 axis could be initiated by lipopolysaccharide, thus trigger cardiomyocytes apoptosis and pyroptosis by activating NLRP3 inflammasome. In the present study, STING overexpression significantly improved cardiac function, and alleviated AB-induced cardiac hypertrophy, fibrosis as well as inflammation. The abnormal protein synthesis within the endoplasmic reticulum could lead to the accumulation of unfolded proteins, thereby giving rise to endoplasmic reticulum stress as well as the unfolded protein response. Endoplasmic reticulum stress has been identified one of the main mechanisms contributing to cardiac remodelling. In hepatocytes, endoplasmic reticulum stress could activate IRF3 via STING, eventually causing hepatocyte apoptosis. Clinical study has disclosed that endoplasmic reticulum stress is activated during cardiac remodelling, which exerts a crucial role in maintaining cell homeostasis. Endoplasmic reticulum stress is also linked to the autophagic response and the endoplasmic reticulum stress-autophagy pathway is involved in pathological cardiac hypertrophy. Based on these studies, we speculate that STING may serve as a bridge between endoplasmic reticulum stress and autophagy.
Apoptotic signaling-dependent disruption of ULK1, a pro-autophagic protein negatively regulating STING, could stimulate STING-dependent IRF3 activation by phosphorylating STING at serine 366 site[32, 33], indicating that STING could directly interact with ULK1. On the other hand, mTOR can phosphorylate ULK1 at its serine 757 site and inhibit its kinase activity, thus blocking autophagy. In this study, STING overexpression enhanced the phosphorylation of ULK1. Hence, we hypothesized that STING may inhibited cardiac remodelling by repressing ULK1-mediated autophagy. But more proof is needed to explore whether the phosphorylated effect of STING on ULK1 is direct or indirect.