Diabetes mellitus is the major risk factor for the development of macrovascular and microvascular complications. It is increasingly recognized that glycemic variability (GV), referring to oscillations in blood glucose levels and representing either short-term or long-term GV, is involved in the pathogenesis of diabetic complications and has emerged as a possible independent risk factor for them. In this review, we summarize the metrics and measurement of GV in clinical practice, as well as comprehensively elaborate the role and related mechanisms of GV in diabetic macrovascular and microvascular complications, aiming to provide the mechanism-based therapeutic strategies for clinicians to manage diabetes mellitus.

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Angiogenesis is critical for re‐establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR‐185‐5p were differently expressed in plasma from patients with ACS by high‐throughput RNA sequencing. The expressional levels of miR‐185‐5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT‐PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR‐185‐5p. In HUVECs, miR‐185‐5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR‐185‐5p inhibitors performed the opposites. Further, the inhibitory effects of miR‐185‐5p up‐regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus‐mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain‐function of miR‐185‐5p by agomir infusion down‐regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR‐185‐5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR‐185‐5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.

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Diabetes mellitus (DM) increases the risk of viral infections especially during the period of poor glycemic controls. Emerging evidence has reported that DM is one of the most common comorbidities in the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, also referred to as COVID-19. Moreover, the management and therapy are complex for individuals with diabetes who are acutely unwell with suspected or confirmed COVID-19. Here, we review the role of antidiabetic agents, mainly including insulin, metformin, pioglitazone, dipeptidyl peptidase-4 (DPP4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists in DM patients with coronavirus infection, addressing the clinical therapeutic choices for these subjects.

-Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, owing to the dysfunction of prostaglandin I2 synthase (PTGIS). Micro RNAs (miRNAs) repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of gene expression. -Nitrovasodilator resistance was induced by nitroglycerin (GTN; 100 mg/kg/day, 3 days) infusion in mice. The responses of aortic arteries to nitric oxide (NO) donors were assessed in organ chamber. The expressional levels of miR-199a/b were assayed by RT-qPCR or FISH. -In cultured HUVECs, NO donors induced miR-199a/b endogenous expression of and downregulated gene expression, both of which were reversed by carboxyl-PTIO or silence of serum response factor. Evidence from computational and luciferase reporter gene analyses indicates that the seed sequence of 976-982 in 3'-UTR of mRNA is a target of miR-199a/b. Gain-functions of miR-199a/b resulting from chemical mimics or adenovirus-mediated overexpression increased mRNA degradation in HEK293 cells and HUVECs. Furthermore, GTN-decreased gene expression was prevented by miR-199a/b antagomirs or was mirrored by the enforced expression of miR-199a/b in HUVECs. In mice, GTN induced the ectopic expression of miR-199a/b in the carotid arterial endothelium, decreased gene expression, and instigated nitrovasodilator resistance, all of which were abrogated by miR-199a/b antagomirs or LNA-anti-miR-199. Importantly, the effects of miR-199a/b inhibitions were abolished by adenovirus-mediated deficiency. Moreover, the enforced expression of miR-199a/b repressed gene expression and impaired the responses of aortic arteries to GTN/sodium nitroprusside/acetylcholine/cinaciguat/riociguat, whereas the exogenous expression of gene prevented nitrovasodilator resistance in mice subjected to GTN infusion or miR-199a/b overexpression. Finally, indomethacin, iloprost, and SQ29548 improved vasorelaxation in GTN-infused mice, while U51605 induced nitrovasodilator resistance. In humans, the increased expressions of miR-199a/b were closely associated with nitrate tolerance. -NO-induced ectopic expression of miR-199a/b in endothelial cells is required for nitrovasodilator resistance via the repression of gene expression. Clinically, miR-199a/b is a novel target for the treatment of nitrate tolerance.

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ObjectiveTo investigate whether 4-hydroxynonenal (4-HNE) regulates asymmetric dimethylarginine (ADMA) metabolism through pathway independent of direct adduct formation with ADMA metabolizing enzyme and the involvement of microRNA (miRNA) miR-21 in human umbilical venous endothelial cells (HUVECs).MethodsCultured HUVECs were treated with 4-HNE (at concentrations of 1, 5, and 10 µM, respectively) or 1‰ DMSO (vehicle control) for 24 h. MiR-21 inhibitor (final concentration of 100 nM) was transfected at 1 h before 4-HNE treatment. HUVECs were also transfected with miR-21 (at concentrations of 50 nM and 100 nM) and cultured for 12, 24, and 48 h, respectively. DDAH mRNA and miR-21 expression in the HUVECs were determined by semi-quantitative real time PCR. DDAH1 and DDAH2 protein expression were analyzed by Western blot. ADMA in the cell medium and cell lysates were analyzed by ELISA. ADMA metabolizing activity of the cell lysates was also determined.ResultsMiR-21 decreased DDAH1 and DDAH2 expression and ADMA metabolic activity significantly, while increased intracellular ADMA accumulation significantly in HUVECs. 10 µM 4-HNE treatment for 24 h increased the expression of miR-21 and intracellular ADMA concentration, decreased the expression of DDAH1/2 mRNA and protein, decreased ADMA metabolizing activity of the cell lysates significantly. MiR-21 inhibitor reversed the inhibitory effects of 4-HNE on DDAH1 expression completely, and partially reversed the changes in ADMA metabolizing activity and intracellular ADMA accumulation challenged by 10 µM 4-HNE.Conclusion4-HNE down-regulates DDAH1 expression and increases intracellular ADMA accumulation in HUVECs through a miR-21-dependent mechanism.