FIG. 6.

Activation of the inflammasome in the heart in response to mitochondrial stress. In response to the metabolic stress of diabetes, including excess FFA and hyperglycemia, damaged mitochondria release excess ROS and oxidized DNA. This response can be exacerbated by ischemia. These danger signals can promote the assembly of the NLRP3 inflammasome, including caspase 1 (casp1), which cleaves pro-IL-1β, to release the mature cytokine. On release, IL-1β can promote additional inflammation, cardiac injury, and fibrosis. Moreover, in the diabetic environment, activation of toll-like receptors by tissue damage or infection can trigger mitochondrial and lysosomal (Ly) stress, leading to inflammasome activation in recruited macrophages and further amplifying the IL-1 response. The excessive release of cytokines exacerbates mitochondrial dysfunction and ROS generation, leading to cardiomyocyte damage and contractile dysfunction.