The Role of PKC-MAPK Signalling Pathways in the Development of Hyperglycemia-Induced Cardiovascular Complications

Abstract

Cardiovascular disease is the most common cause of death among diabetic patients worldwide. Hence, cardiovascular wellbeing in diabetic patients requires utmost importance in disease management. Recent studies have demonstrated that protein kinase C activation plays a vital role in the development of cardiovascular complications via its activation of mitogen-activated protein kinase (MAPK) cascades, also known as PKC-MAPK pathways. In fact, persistent hyperglycaemia in diabetic conditions contribute to preserved PKC activation mediated by excessive production of diacylglycerol (DAG) and oxidative stress. PKC-MAPK pathways are involved in several cellular responses, including enhancing oxidative stress and activating signalling pathways that lead to uncontrolled cardiac and vascular remodelling and their subsequent dysfunction. In this review, we discuss the recent discovery on the role of PKC-MAPK pathways, the mechanisms involved in the development and progression of diabetic cardiovascular complications, and their potential as therapeutic targets for cardiovascular management in diabetic patients.

Keywords: ERK1/2; JNK; cardiac remodelling; p38; vascular dysfunction.

Figure 1

Classification and structural characteristics of PKC isoforms. Although the catalytic domain of PKC is conserved, the three subgroups have different regulatory domains. The classical PKC isoforms (cPKC) share all typical regulatory features: the autoinhibitory pseudosubstrate motif, two DAG-binding C1 domains and the calcium-binding C2 domain. Novel PKC isoforms (nPKC) lack a calcium-binding motif but contain an extended N-terminal domain that can receive regulatory signals, and they are still being regulated by DAG. On the other hand, the catalytic activity of atypical PKC isoforms (aPKC) is independent of DAG and calcium.

Figure 2

Mechanism of DAG–PKC activation. Hyperglycaemia induces mainly the de novo pathway of DAG synthesis from glucose to glycerol 3-phosphate with subsequent PKC activation. ROS, reactive oxygen species; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; FDP, fructose 1,6-diphosphate; F6P, fructose 6-phosphate; GAP, glyceraldehyde 3-phosphate; G3P, glycerol 3-phosphate; G6P, glucose 6-phosphate; lysoPA, lysophosphatidic acid; PA, phosphatidic acid; PKC, protein kinase C; MAPK, mitogen-activated protein kinase. Arrows represent the subsequent event/product in the pathway; red arrow represents increased production.

Figure 3

MAPKs cascades: MAPK signalling cascades are organized hierarchically into three-tiered modules. MAPKs are phosphorylated and activated by MAPK-kinases (MAP2Ks), which in turn are phosphorylated and activated by MAPKK-kinases (MAP3Ks). The MAP3Ks are in turn activated by interaction with the family of small GTPases and/or other protein kinases, connecting the MAPK module to cell surface receptors or external stimuli.

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.