2.1 Increased vascular inflammation in ECs
During hyperglycaemia, binding of AGEs to RAGE elevates adhesion
molecule expression, production of cytokines and growth factors via the
activation of ERK, JNK, and phosphoinositol 3-kinase (PI3k) pathways.
AGEs directly stimulate monocytes to produce inflammatory mediators like
interleukins (ILs) and TNF-α, and thereby further enhance local
inflammation of the vascular wall (Jin et al. , 2018). Moreover,
excessive production of ROS induces vascular inflammation in ECs via
upregulating intercellular adhesion molecule 1 (ICAM-1) and vascular
cell adhesion molecule 1 (VCAM-1) (Daiber et al. , 2020). The
oxidative stress triggers cytokine secretion mainly in an
“inflammasome-dependent” manner (Bai et al. , 2020). Briefly,
ROS activate NF-κB and upregulate the expression level of NOD-like
receptor containing pyrin domain 3 (NLRP3) inflammasome as well as
pro-IL-1β. Then, NLRP3 inflammasome is activated through assembling of
NLRP3, caspase-1 and apoptosis-associated speck-like protein containing
a CARD (caspase activation and recruitment domain), forming a complex
for the final production of active caspase-1, IL-1β and IL-18. This
process is also accelerated by ROS (Ferrucci et al. , 2018; Toldoet al. , 2021). Intriguingly, pro-inflammatory mediators released
during inflammation like TNF-α can induce ROS production, thus promoting
the “vicious circle” of oxidative stress and inflammation (Yuanet al. , 2019).