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p21-activated kinase 1 (PAK1) as a therapeutic target for cardiotoxicity

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Abstract

The p21-activated kinase 1 (PAK1), an effector protein of the small G protein Rac and cell division cycle protein 42 (Cdc42), is highly expressed in cardiac tissue. Although a large number of studies have explored the molecular basis and biological function of PAK1, research on PAK1 as a therapeutic target for cardiotoxicity remains in a stage of continuous innovation, and further clarification of its role in cardiotoxicity is required. In this review, we examine the important role of PAK1 in the programmed death (apoptosis, autophagy, and pyroptosis) of cardiomyocytes, and its involvement in oxidative stress and inflammatory responses, which are based on mitochondrial dysfunction and calcium homeostasis imbalance. We also summarize the related signaling pathways through which PAK1 may cause oxidative stress and inflammatory response in cardiotoxicity, and discuss the PAK1-mediated contributions of the gut microbiome and micro RNAs to cardiotoxicity. We propose that PAK1 holds great promise for novel therapeutic strategies to facilitate improvements in the treatment of complex and diverse cardiovascular diseases.

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The data used to support the findings of this study are included within the article.

Abbreviations

Cdc42:

Cell division cycle 42 (GTP-binding protein, 25 kDa)

mTOR:

Mammalian target of rapamycin

Akt:

Protein kinase B

AMPK:

Adenosine 5′-monophosphate (AMP)-activated protein kinase

BAD:

Bcl-2 antagonist of cell death

Bcl-2:

B-cell lymphoma 2

Ca2 + :

Calcium ions

Ccnd1:

Cyclin D1

CoB1:

Cochlioquinone B derivative

CVDs:

Cardiovascular diseases

eNOS:

Endothelial nitric oxide synthase

EPCs:

Endothelial progenitor cells

Erk1/2:

Extracellular signal-regulated kinase 1/2

ETC:

Electron transport chain

FasL:

Fas ligand

Foxo:

Forkhead box

FTY720:

Fingolimod

Grb2:

Growth-factor receptor-bound protein 2

HG:

High glucose

HIF-1A:

Hypoxia inducible factor-1A

IKK:

IκB kinase

IL-1β:

Interleukin-1β

IL-3:

Interleukin 3

JNK:

C-Jun NH2-terminal kinase

Klf2:

Kruppel-like factor 2

LCGTs:

Large clostridial glucosylating toxins

LPS:

Lipopolysaccharide

MAPKs:

Mitogen-activated protein kinases

miRNA:

MicroRNA

MKP1:

Mitogen-activated protein kinase phosphatase-1

MLCK:

Myosin light chain kinase

mPTP:

Mitochondrial permeability transition pore

NCX:

Na +/Ca2+ exchanger

NF-κB:

Nuclear factor kappa-B

NLRP3:

NLR family pyrin domain containing 3

NOX:

NADPH oxidase

Pak1:

P21-activated kinase 1

PAKs:

The p21-activated kinases

PAMPs:

Pathogen-associated molecular patterns

PCD:

Programmed cell death

PDE2:

Phosphodiesterases-2

PDGF:

Platelet-derived growth factor

PDK1:

3-Phosphoinositide-dependent protein kinase 1

PGAM-B:

Phosphoglycerate mutase-B

PI3K:

Phosphatidylinositol 3-kinase

PP2A:

Protein phosphatase 2A

PRRs:

Pattern recognition receptors

Rac1:

Ras-related C3 botulinum toxin substrate 1

Ras/Raf/MEK/ERK:

A mitogen-activated protein kinase, MAPK pathway

ROS:

Reactive oxygen species

SCFAs:

Short-chain fatty acids

SIRT1:

Sirtuin 1

Src:

Src kinase

SubAB:

Subtilase cytotoxin

TAK1:

TGFβ-activated kinase 1

TMAO:

Trimethylamine N-oxide

TNFα:

Tumor necrosis factor-α

TRAF6:

TNF receptor-associated factor 6

UA:

Urolithin A

VEGF:

Vascular endothelial growth factor

VMs:

Ventricular myocytes

Wasp:

Wiskott–Aldrich syndrome protein

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Acknowledgements

We thank Michelle Kahmeyer-Gabbe, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.

Funding

This research was funded by grants from National Undergraduate Innovation and Entrepreneurship Training Program (202110632016), the fund (KeyME-KeyME-2020–004) of Key Laboratory of medical electrophysiology, Luzhou Municipal People’s Government—Southwest Medical University Science and Technology Strategic Cooperation (2021LZXNYD-J33) and Gulin County People's Hospital—Affiliated Hospital of Southwest Medical University Science and Technology strategic Cooperation (2022\GLXNYDFY13).

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  1. The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China

    Ping Guo, Yufeng Liu, Jingrong Feng, Shihang Tang & Fanyan Wei

  2. Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

    Jian Feng

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Guo, P., Liu, Y., Feng, J. et al. p21-activated kinase 1 (PAK1) as a therapeutic target for cardiotoxicity. Arch Toxicol 96, 3143–3162 (2022). https://doi.org/10.1007/s00204-022-03384-1

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