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

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.

Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity

“…Obesity and diabetes are associated with increased ROS production, which is believed to be the link to the pathogenesis of metabolic related complications [49]. Increased ROS levels activate the NLRP3 inflammasome pathway and increase production of inflammatory cytokines which, in-turn, increase ROS production [50]. Previous studies showed that high fat diets induced retinal oxidative stress, which supports our results [5].…”

Eucalyptol alleviates inflammation and pain responses in a mouse model of gout arthritis

“…We further explored the mechanisms of how eucalyptol inhibited NLRP3 inflammasome activation and IL‐1β production in gout arthritis. ROS and oxidative stress play an important role in mediating NLRP3 inflammasome activation (Sharma et al, ). We then examined whether reducing ROS may produce similar effects as eucalyptol under gout condition.…”

Melatonin and inflammation—Story of a double‐edged blade

“…A further peculiarity of AD has emerged by its relationship to brain insulin resistance, which was shown to represent an early event in the AD etiology . Insulin resistance, which is a hallmark of type 2 diabetes, has a strong relationship to low‐grade, sterile inflammation, as shown, for example, by substantial upregulation of IL‐6, and activation of the NLRP3 inflammasome . Whether brain insulin resistance has consequences similar to those in type 2 diabetes, or whether it may represent a separate type of pathology referred to as type 3 diabetes, remains to be a matter of debate.…”