Disruption of TAB1/p38α Interaction Using a Cell-permeable Peptide Limits Myocardial Ischemia/Reperfusion Injury

Abstract

Targeting the adaptor protein (transforming growth factor-β (TGF-β)-activated protein kinase 1 (TAK1)-binding protein 1) (TAB1)-mediated non-canonical activation of p38α to limit ischemia/reperfusion (I/R) injury after an acute myocardial infarction seems to be attractive since TAB1/p38α interaction occurs specifically in very limited circumstances and possesses unique structural basis. However, so far no TAB1/p38α interaction inhibitor has been reported due to the limited knowledge about the interfaces. In this study, we sought to identify key amino acids essential for the unique mode of interaction with computer-guided molecular simulations and molecular docking. After validation of the predicted three-dimensional (3-D) structure of TAB1/p38α complex, we designed several peptides and evaluated whether they could block TAB1/p38α interaction with selectivity. We found that a cell-permeable peptide worked as a selective TAB1/p38α interaction inhibitor and decreased myocardial I/R injury. To our knowledge, this is the first TAB1/p38α interaction inhibitor.

Ginkgo biloba extract prevents acute myocardial infarction and suppresses the inflammation- and apoptosis-regulating p38 mitogen-activated protein kinases, nuclear factor-κB and B-cell lymphoma 2 signaling pathways

“…TGF-β1 expression activity in cardiac muscle tissues of myocardial infarction rats was demonstrated to be markedly enhanced (26). Corresponding MAP3K7, p38 MAPK, and p-p38 MAPK protein activity were also clearly enhanced (26). The possible underlying mechanism involves TGF-β1 activating MAP3K7, thus causing p38 MAPK to be phosphorylated into p-p38 MAPK and enhancing inflammatory factor expression levels in rats, finally resulting in cardiac hypertrophy, interstitial fibrosis, serious cardiac insufficiency, myocardial apoptosis or mortality (25).…”

“…In addition, TGF-β1 is involved in stimulating tissue fibrosis, causing increases in fibrocytes, MMPs, collagen deposition and fiber binding proteins, and results in ventricular remodeling (23). TGF-β1 expression activity in cardiac muscle tissues of myocardial infarction rats was demonstrated to be markedly enhanced (26). Corresponding MAP3K7, p38 MAPK, and p-p38 MAPK protein activity were also clearly enhanced (26).…”

G protein–coupled receptors activate p38 MAPK via a non-canonical TAB1–TAB2– and TAB1–TAB3–dependent pathway in endothelial cells

“…In addition, the mechanisms by which GPCR-stimulated TAB1-induced p38 MAPK signaling controls various inflammatory responses including induction of cytokine production and endothelial barrier disruption remains poorly understood and warrants further exploration. Finally, in vivo studies have documented the relevance of TAB1-p38␣ activation in various disease settings including myocardial ischemia (13,16,44), indicating that TAB1-dependent p38 activation will be likely important for endothelial dysfunction in vivo. A recent paper further showed that disruption of TAB1-p38␣ interaction in vivo reduced myocardial ischemic injury (14), suggesting that the development of small molecules targeting the TAB1-p38␣ interface may provide a specific therapeutic intervention with limited side effects, not otherwise achievable with global p38 inhibition.…”

Cell-based peptide screening to access the undruggable target space

“…This includes local application of the peptides e.g. by direct injection into the brain leading to reduced cell damage in a stroke model [54] or decreased myocardial I/R injury [55,10] targeting two different proteins (JNK1, BH4). Another example is the protein kinase C delta inhibiting peptide Tat-deltaV-1injected into the internal carotid artery, which improved pathology after cerebral reperfusion injury [56,57].…”