The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

Keywords: AA, amino acids; AAD, aortic aneurysm and dissection; AKT, protein kinase B; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; Ang II, angiotensin II; CBD, C-binding domain; CDG, c-di-GMP; CDNs, cyclic dinucleotides; CTD, C-terminal domain; CTT, C-terminal tail; CVDs, cardiovascular diseases; Cardiovascular diseases; Cys, cysteine; DAMPs, danger-associated molecular patterns; Damage-associated molecular patterns; DsbA-L, disulfide-bond A oxidoreductase-like protein; ER stress; ER, endoplasmic reticulum; GTP, guanosine triphosphate; HAQ, R71H-G230A-R293Q; HFD, high-fat diet; ICAM-1, intracellular adhesion molecule 1; IFN, interferon; IFN-I, type 1 interferon; IFNAR, interferon receptors; IFNIC, interferon-inducible cells; IKK, IκB kinase; IL, interleukin; IRF3, interferon regulatory factor 3; ISGs, IRF-3-dependent interferon-stimulated genes; Inflammation; LBD, ligand-binding pocket; LPS, lipopolysaccharides; MI, myocardial infarction; MLKL, mixed lineage kinase domain-like protein; MST1, mammalian Ste20-like kinases 1; Metabolic diseases; Mitochondria; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor-kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; NO2-FA, nitro-fatty acids; NTase, nucleotidyltransferase; PDE3B/4, phosphodiesterase-3B/4; PKA, protein kinase A; PPI, protein–protein interface; Poly: I.C, polyinosinic-polycytidylic acid; ROS, reactive oxygen species; SAVI, STING-associated vasculopathy with onset in infancy; SNPs, single nucleotide polymorphisms; STIM1, stromal interaction molecule 1; STING; STING, stimulator of interferon genes; Ser, serine; TAK1, transforming growth factor β-activated kinase 1; TBK1, TANK-binding kinase 1; TFAM, mitochondrial transcription factor A; TLR, Toll-like receptors; TM, transmembrane; TNFα, tumor necrosis factor-alpha; TRAF6, tumor necrosis factor receptor-associated factor 6; TREX1, three prime repair exonuclease 1; YAP1, Yes-associated protein 1; cGAMP, 2′,3′-cyclic GMP–AMP; cGAS; cGAS, cyclic GMP–AMP synthase; dsDNA, double-stranded DNA; hSTING, human stimulator of interferon genes; mTOR, mammalian target of rapamycin; mtDNA, mitochondrial DNA.

Graphical abstract

Figure 1

Mechanism of activation of the cGAS–STING cytosolic DNA sensing pathway. Double-stranded DNA, RNA, and RNA–DNA hybrids from exogenous and endogenous sources are sensed by cGAS. After dsDNA/dsRNA binding on cGAS, cGAS utilizes ATP and GTP to synthesize cGAMP. cGAMP binds to STING at the ER. Upon cGAMP binding, STING traffics from the ER to the Golgi apparatus and finally interact with TBK1 and IRF3 and NF-κB, culminating in IFN-I and pro-inflammatory cytokines production. In addition, aside cGAMP, ER stress can initiate STING activation, leading to IFN-I and pro-inflammatory cytokines production.

Figure 2

Basic features of cGAS structure and ligand binding dynamics. (A) Schematic diagram of human cGAS functional domains; (B) Left, the crystal structure of ligand-free apo human-cGAS (“side view,” PDB ID: 4MKP). Right, the crystal structure of ligand-free human-cGAS dimer (“upright view,” PDB ID: 4LEY); (C) Globular catalytic domain of human cGAS in complex with dsDNA, ATP, and GTP (PDB ID: 4KB6). PDB: Protein data bank; aa: amino acids.

Figure 3

Basic features of STING structure and molecular mechanism of STING activation. (A) Schematic diagram of human STING functional domains; (B) Molecular mechanism model showing the binding and complex formation between cGAMP and human STING crystal structure dimer (PDB ID: 4LOH) (blue and red colors-STING monomers); (C) Full-length apo human STING crystal structure (PDB ID: 6NT5) (red-orange: TM1; golden yellow: TM2; lemon green: TM3; light green: TM4). PDB: protein data bank; CBD: C-binding domain; CTT: C-terminal tail; TM: transmembrane; aa: amino acids.

Figure 4

STING signaling activation mediates heart diseases. In ischemic myocardial infarction, massive ischemic cardiomyocyte death leads to the aberrant liberation of DNA. This DNA is sensed by cGAS in macrophages, leading to the STING–TBK1–IRF3 signaling activation. Activated IRF3 translocates into the nucleus to induce the transcription expression of type one IFNs, causing recurrent expression of ISGs and subsequent recruitment and differentiation of leukocytes. On the other hand, in cardiac hypertrophy, ER stress occurs in cardiomyocytes and subsequently activates STING, leading to TBK1–IRF3 and -NF-κB downstream signaling pathways activation. Active IRF3 and NF-κB then enter the nucleus, where IRF3 function to switch on the expression of type one IFNs, while NF-κB promotes pro-inflammatory cytokines expression. Expressed pro-inflammatory cytokines act to enhance TGF-β1 levels leading to fibrosis.

Figure 5

The DNA-sensing cGAS–STING pathway activation-induces endothelial and vascular dysfunction. Metabolic stress-mediated upregulation of free fatty acids and the cytosolic accumulation of LPS triggers mitochondria damage. These actions destabilize mtDNA compartmentalization and promote mtDNA release into endothelial cytosol. In turn, the mtDNA is sensed by cGAS, which subsequently activates the STING–TBK-1 pathway, leading to the phosphorylation of IRF3 and LATS1/2. Active IRF3 translocate to the nucleus to promote transcription expression of ICAM1, MST1, and cytokines, including IFN-I. Expressed MST1 together with activated STING–TBK-1 function to suppress the Hippo pathway by stimulating phosphorylation of LATS1/2. This represses cyclin D-mediated endothelial cell proliferation and vascular repair. In addition, mutations in the STING-encoding gene can directly induce endothelial dysfunction through the progressive stimulation of endothelial activation and adhesion molecules, pro-inflammatory cytokines and factors, endothelial cell-death, etc., to drive pathological vascular conditions in SAVI patients.

Figure 6

Obesity-induced activation of DNA-sensing cGAS–STING signaling pathway mediates inflammation and metabolic abnormalities. The metabolic disorder (obesity) destabilizes mtDNA localization by inhibiting DsbA-L. Decreased DsbA-L promotes mtDNA liberation, which is sensed by cGAS and, in turn, activates the cGAS–STING–TBK-1 pathway. Besides active STING–TBK-1, LPS, and poly: I.C could activate TLR4 and TLR3 receptors to stimulate the phosphorylation of IRF3. IRF3 and NF-κB activation induce the transcription expression of pro-inflammatory cytokines (TNFα, IFNα, MCP-1, IL-18) while the phosphorylation of PDE3B/4 by active TBK-1 inhibits cellular cAMP levels. The increased expressions of pro-inflammatory cytokines contribute to inflammation-mediated metabolic dysfunction leading to insulin resistance. The reduced cAMP levels suppress PKA signaling contributing to the abrogation of thermogenesis (heat production) in adipose tissues.