MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

Abstract

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

Figure 1

Model of the role of MAPK cascades in cardiomyocyte hypertrophy. In response to pressure overload, there is an intramyocardial release of ligands such as endothelin-1 (ET-1), angiotensin II (AngII) and norepinephrine (NE), growth factors such as fibroblast growth factor 1 (FGF1), and cytokines. These extracellular factors bind to and activate transmembrane G protein-coupled receptors (GPCR), receptor tyrosine kinases (RTK) and cytokine receptors (not depicted). Activated transmembrane receptors, in turn, directly activate intracellular signaling proteins, including G proteins (Gq/11) and the Grb2/SoS complex that promote activation of MAPK cascades and the Ca⁺⁺/Calmodulin (CaM)-Calcineurin A (CnA)-NFAT3/4 cascade. Activation of these signaling cascades modulates the growth of cardiomyocytes in the manner depicted. Specifically, ERK MAPK phosphorylates a variety of targets that may contribute to cardiomyocyte growth, including the transcription factors Elk-1 and GATA4, and several proteins that regulate the translational machinery, including tuberin (TSC2 gene product), Mnk1 and p90^RSK. On the other hand, JNK and p38 MAPK phosphorylate NFAT family members, resulting in inhibition of the calcineurin-NFAT hypertrophic pathway.

Figure 2

Model of the role of MAPK cascades in pathological cardiac remodeling after myocardial infarction. After myocardial infarction, there is a local release of ligands such as norepinephrine (NE), cytokines, growth factors such as FGF1, and reactive oxygen species (ROS) that leads to the activation transmembrane receptors and intracellular MAPK cascades. ROS may modify the activity of the MKKK ASK1 by blocking the ability of thioredoxin to inhibit ASK1. The activation of the MKKK-MKK3/6-p38α MAPK and the ASK1-MKK4/7-JNK1/2 cascades promotes pathological cardiac remodeling that includes cardiomyocyte apoptosis, inhibition of cardiomyocyte mitosis, inflammation and fibrosis. Specifically, p38α MAPK promotes cardiomyocyte mitosis by inhibiting the activity or expression of the anti-apoptotic proteins Bcl-2 and Bcl-x_L.

Figure 3

Simplified model of macrophage foam cell formation in the arterial subintimal space. In response to vascular injury, monocytes are recruited to the intimal surface of arteries where they adhere and invade the vessel, differentiating into macrophages. In the subintimal space, macrophages are exposed to oxidized low density lipoprotein (oxLDL) that binds to the transmembrane protein CD36. Binding of oxLDL to CD36 triggers the activation of src-family kinases such as Lyn and MEKK2. Activation of Lyn and possibly MEKK2 leads to the activation of JNK2 and also p38α MAPK. Through largely undetermined mechanisms, activation of JNK2 and p38α MAPK promote the internalization of oxLDL either via CD36, scavenger receptor A (SR-A) or through other scavenger receptors. JNK2 promotes the phosphorylation of SR-A and this may lead to SR-A internalization while it is associated with modified LDL. Activation of MAPK cascades in macrophages may also modulate cholesterol efflux pathways.

Figure 4

Model of smooth muscle cell proliferation in neointima formation after vascular injury. In response to arterial injury that includes endothelial denudation and stretch, there is a local release of ligands such as endothelin-1 (ET-1), angiotensin II (AngII) and thrombin, growth factors (GFs), and cytokines that bind to transmembrane receptors. These receptors include G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and cytokine receptors (not depicted) that activate intracellular signaling proteins such as G proteins (Gq/11) and the Grb2/SOS complex. In turn, intracellular MAPK cascades are activated that ultimately leads to vascular smooth muscle cell migration (VSMC) into the intima and proliferation, resulting in neointima formation. The activation of p38α MAPK in vascular smooth muscle cells promotes the hyperphosphorylation of Rb and the expression of MCM6 that both contribute to cell proliferation.