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Review
. 2018 Feb 20:9:114.
doi: 10.3389/fphys.2018.00114. eCollection 2018.

Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications

Arpeeta Sharma  1 , Mitchel Tate  2 , Geetha Mathew  3 , James E Vince  4   5 , Rebecca H Ritchie  2 , Judy B de Haan  1
Affiliations
Review

Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications

Arpeeta Sharma et al. Front Physiol. .

Abstract

It is now increasingly appreciated that inflammation is not limited to the control of pathogens by the host, but rather that sterile inflammation which occurs in the absence of viral or bacterial pathogens, accompanies numerous disease states, none more so than the complications that arise as a result of hyperglycaemia. Individuals with type 1 or type 2 diabetes mellitus (T1D, T2D) are at increased risk of developing cardiac and vascular complications. Glucose and blood pressure lowering therapies have not stopped the advance of these morbidities that often lead to fatal heart attacks and/or stroke. A unifying mechanism of hyperglycemia-induced cellular damage was initially proposed to link elevated blood glucose levels with oxidative stress and the dysregulation of metabolic pathways. Pre-clinical evidence has, in most cases, supported this notion. However, therapeutic strategies to lessen oxidative stress in clinical trials has not proved efficacious, most likely due to indiscriminate targeting by antioxidants such as vitamins. Recent evidence now suggests that oxidative stress is a major driver of inflammation and vice versa, with the latest findings suggesting not only a key role for inflammatory pathways underpinning metabolic and haemodynamic dysfunction in diabetes, but furthermore that these perturbations are driven by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This review will address these latest findings with an aim of highlighting the interconnectivity between oxidative stress, NLRP3 activation and inflammation as it pertains to cardiac and vascular injury sustained by diabetes. Current therapeutic strategies to lessen both oxidative stress and inflammation will be emphasized. This will be placed in the context of improving the burden of these diabetic complications.

Keywords: NLRP3 inflammasome; diabetic atherosclerosis; diabetic cardiomyopathy; diabetic complications; diabetic nephropathy; inflammation; inflammatory cytokines; oxidative stress.

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Figures

Figure 1
Figure 1
The role of the NLRP3 inflammasome and interconnectivity with oxidative stress and inflammation in the development of complications in diabetes. Metabolic changes in diabetes including insulin resistance, hyperlipidaemia and hyperglycaemia (and the subsequent production of DAMPs), lead to an increase in inflammation, oxidative stress and NLRP3 inflammasome activation and subsequent development of diabetic complications including diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy. DAMPs, damage associated molecular patterns; RAGE, receptor for advanced glycation end-products; IAPP, islet amyloid polypeptide protein.
Figure 2
Figure 2
A diagrammatic representation of NLRP3 inflammasome activation. NLRP3 activation is a distinct two-step process requiring a priming (“signal 1”) signal and an activating (“signal 2”) signal. The priming signal is usually initiated by PAMPs (LPS) that bind to toll-like receptors (TLR) and induce expression of NLRP3, pro IL-1β, and pro IL-18. The second activating signal is required for NLRP3 inflammasome assembly, by binding of NLPR3 and pro caspase-1 to adaptor protein ASC. Activating signals include potassium efflux through ion channels and cathepsin release by lysosomal degradation. In settings of diabetes, excessive ROS production in the cytosol and mitochondria has been implicated in NLRP3 inflammasome activation. Following NLRP3 assembly and activation, caspase-1 undergoes proteolytic cleavage and further processes pro IL-1β and pro IL-18 into their mature forms for secretion. In addition, caspase-1 also cleaves GSDMD which results in plasma membrane pore formation and pyroptototic cell death. PAMPs, pathogen associated molecular patterns; DAMPs, damage associated molecular patterns; LPS, lipopolysaccharides; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); GSDMD, gasdermin D; CARD, caspase recruitment domain; PYD, PYRIN domain; NACHT, a domain containing NAIP, CIITA, HET-E and TEP1 domains.
Figure 3
Figure 3
Graphic summary of NLRP3 activation to promote atherogenesis. In endothelial cells, atheroprone or disturbed flow activates sterol regulatory element binding protein 2 (SREBP2) which induces expression of the ROS producing enzyme Nox2 and NLRP3. In macrophages, NLRP3 activation is mediated by the increased presence of glucose-mediated ROS, ox-LDL and cholesterol crystals in diabetic and atherogenic settings. The resultant secretion of IL-1β and IL-18 by both cell types in turn contribute to endothelial dysfunction, macrophage recruitment, migration and activation, and the upregulation of inflammatory mediators including VCAM-1, MCP-1, and NF-κB, leading to progression of atherosclerosis.
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