Emerging Clues of Regulatory Roles of Circular RNAs through Modulating Oxidative Stress: Focus on Neurological and Vascular Diseases

Table 1

The evidence of regulatory roles of circRNAs in various diseases under oxidative stress.

Evidence from basic research
Cell line/animal	Disease model/treatment	Sample	circRNA	Alteration of expression	Various roles in the pathophysiological mechanism	Reference
HT22 cells	OGD/R	Cell	mmu-circRNA-015947	Upregulated	May participate in apoptosis-related, metabolism-related, and immune-related pathways	[62]
CMVECs	Oxidative stress induced by H2O2	Cell	circHIPK3	Upregulated	Overexpression significantly decreased apoptosis and protected CMVECs against H2O2-induced oxidative damages	[78]
HUVECs	Oxidative stress induced by HG	Cell	circBPTF	Upregulated	Regulate HG-induced HUVEC dysfunction, including apoptosis, inflammation, and oxidative stress	[80]
SH-SY5Y cells	Oxidative stress induced by H2O2	Cell	circPRKCI	Downregulated	Alleviate the cytotoxicity induced by H2O2	[92]
ARPE-19 cells	Oxidative stress induced by HG	Cell	circRNA_0084043	Upregulated	May enhance malondialdehyde content and decrease activities of SOD and glutathione peroxidase, resulting in enhancing the oxidative stress in HG-indicated human retinal pigment epithelium ARPE-19 cells	[102]
Rat Schwann RSC96 cells	Oxidative stress induced by HG	Cell	circACR	Downregulated	Relieve the oxidative stress caused by HG	[95]
Vascular smooth muscle cells	Hyperglycemia stimulation	Exosomes	circRNA-0077930	(See the right column)	Its overexpression increases the lactate dehydrogenase activity, reduces the antioxidative stress marker (SOD) activity, and induces senescence	[82]
H9c2 cells	100 μM H2O2 treatment	Cell	circNCX1	Upregulated	Lead to the death of cardiomyocytes in vitro and in vivo, acting as an endogenous miR-133a-3p sponge	[101]
H9c2 cells	Oxidative stress induced by H2O2	Cell	circNFIX	Downregulated	Facilitates oxidative stress-induced H9c2 cells apoptosis	[107]
Mesangial cells	High glucose- (HG-) treated	Cell	circLRP6	Upregulated	Regulates HG-induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells via sponging miR-205, upregulating HMGB1, and activating TLR4/NF-κB pathway	[108]
Rat	ICH	Cortical tissues around the hematoma	rno_circRNA_011054; rno_circRNA_005098; rno_circRNA_012556	Upregulated; Downregulated	Promising targets for therapeutic intervention of ICH	[58]
Chicken	NH3 treatment	Thymuses	circRNA-SMC6	(See the right column)	Correlated with OXR1, which can protect cells from oxidative damage	[109]
Mouse	Nrf2 knockout	Substantia nigra	mmu-circRNA-32463; mmu-circRNA-015216	Upregulated; Downregulated	A potential regulator of Nrf2-mediated neuroprotection against oxidative stress	[88]
Mouse	Nrf2 knockout	Corpus striatum	mmu-circRNA-017077	Downregulated	Participate in Nrf2-mediated Fas-induced apoptosis in a variety of neurological diseases associated with oxidative stress	[88]
Mouse	tMCAO	Cortical tissue	circ_008018	Upregulated	Result in brain tissue damage and neurological deficits	[63]
Mouse	Oxidative stress induced by H2O2	Cardiac endothelial cells	circHIPK3	Enriched in exosomes	Promote accelerated cell cycle progression and proliferation	[79]
Mouse	tMCAO	Cell lysates	circ_008018; circ_015350; circ_016128; circ_011137; circ_001729; circ_006696	Upregulated; 6 hours reperfusion after transient MCAO; Downregulated; 6 hours reperfusion after transient MCAO	Might have functional consequences in controlling the secondary brain damage and neurological dysfunction	[57]
Mouse	tMCAO	Cell lysates	circDLGAP4	Downregulated	Decrease neurological deficits and infarct areas and blood-brain barrier (BBB) damage	[60]
Mouse	Diabetic retinopathy	Cell lysates	circZNF609	Upregulated	Capillary degeneration and pathological angiogenesis	[73]
Rat	Coronary atherosclerosis	Coronary artery tissue	circANRIL	In the empty vector and overexpressed cANRIL groups, atherosclerotic plaques and thrombi appeared	Reduced cANRIL expression could prevent coronary AS by reducing vascular EC apoptosis and inflammatory factor expression	[75, 76]
Mouse	Hypertrophy and heart failure induced by ISO treatment	Cardiomyocytes	mm9_circ_012559, circHRCR	Downregulated	Inhibits cardiac hypertrophy and heart failure by targeting miR-223 and ARC	[99]
Mouse	MI	Mouse myocardial tissues and mouse blood samples	circCDR1	Upregulated	May aggravate the oxidative stress in neuronal cells	[94]
Rat	Renal ischemia-reperfusion	Mouse kidney tissues	circAKT3	(See the right column)	Involve RI/R injury progression through regulating miR-144-5p/Wnt/β-catenin pathway and oxidative stress	[103]
Rats	I/R pretreatment with salidroside	Rat heart tissues	circ_0000064	Upregulated	Have a protective effect on myocardial ischemia-reperfusion injury	[98]
Evidence from clinical research
Disease	Sample	Treatment	circRNA	Alteration of expression	Various roles in the pathophysiological mechanism	Reference
AIS	Plasma from patients	N/A	circDLGAP4	Downregulated	Decrease neurological deficits and infarct areas and blood-brain barrier (BBB) damage	[60]
AIS	Plasma from patients	N/A	circFUNDC1, circPDS5B, circCDC14A	Upregulated	Serve as biomarkers for AIS diagnosis and prediction of stroke outcomes	[61]
Acute carotid-related cerebrovascular ischemia	Plasma from patients	N/A	The ratio of circRNA-284/miR-221	Increased	Detect plaque rupture and stroke, as biomarkers in cardiovascular disease	[64]
Parkinson’s disease	Postmortem brain tissues from patients	N/A	circSLC8A1	Upregulated	In oxidative stress, oxidation itself may increase the circulation of circSLC8A1 in neurons and reduce the expression of SLC8A1 protein	[91]
Glioma	In glioma tissues from patients and cells (T98G and LN229)	N/A	circSCAF11	Upregulated	Its knockdown repressed cell proliferation and invasion	[104]
Intestinal infarction	In the intestinal mucosal tissues of mice and patients undergoing surgery for acute mesenteric arterial embolism, strangulated intestinal obstruction, or incarcerated hernia	I/R	circPRKCB	Upregulated	circPRKCB silencing or miR-339-5p overexpression significantly downregulated p66Shc expression and attenuated oxidative stress levels and I/R injury	[105]
Atherosclerotic plaques	SMCs and CD68-positive macrophages from patients	N/A	circANRIL	Upregulated	May alter RNA function and confer atheroprotection	[9]
ARC	Lens epithelial cells from patients	N/A	circHIPK3	Downregulated	Under oxidative stress, circHIPK3 silencing increased the number of cell death and inhibited cell proliferation	[77]
Human dental pulp stromal cells (a mesenchymal stromal cell source for regenerative therapy)	Human dental pulp stromal cells	Oxidative stress induced by H2O2	hsa_circ_0000257	Upregulated	The hsa_circ_0000257/hsa-miR-9-5p/SIRT1/p53 regulatory axis is likely a novel molecular pathway regulating oxidative stress in hDPSCs	[110]

Abbreviations: AIS: acute ischemic stroke; ARC: age-related cataract; CMVECs: cardiac microvascular endothelial cells; H₂O₂: hydrogen peroxide; HUVECs: human umbilical vein endothelial cells; ICH: intracerebral hemorrhage; I/R: ischemia-reperfusion; MI: myocardial infarction; Nrf2: nuclear factor erythroid 2-related factor 2; NH₃: ammonia; HG: high glucose; OGD/R: oxygen-glucose deprivation/reoxygenation; SMCs: smooth muscle cells; SOD: superoxide dismutase; tMCAO: transient middle cerebral artery occlusion.