Figure 4.

Proposed mechanisms involved in the pathogenesis of diabetic cardiovascular complications via the PKC-MAPK pathway. Persistent hyperglycemia induces de novo production of diacylglycerol (DAG), which along with reactive oxygen (ROS), would induce the activation of PKC. Hyperglycemia also generates ROS and nitrogen species (RNS) in excess via NADPH oxidase, generating oxidative stress in the cardiac and vascular tissues. By activating Raf dependently and independently of Ras activation, PKC phosphorylates MAP3Ks of the MAPK subfamilies cascades. Following a stimulation, activation of MAPK requires a three-tiered kinase cascade; in which a MAPK kinase kinase (MAPKKK, MEKK, MAP3K or MKKK) activates a MAPK kinase (MAPKK, MEK, MAP2K or MKK), which in turn activates the targeted MAPKs (ERK1/2, JNK and p38) through serial phosphorylation. Uncontrolled activation of MAPKs induces inflammation and cell apoptosis, leading to pathologic cardiac remodelling and vascular dysfunction. Arrows represent the subsequent event/product in the pathway; tappered line represents inhibition action; dotted tappered line represents halted inhibition action.