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Phytochemicals and endothelial dysfunction: recent advances and perspectives

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Abstract

Endothelial dysfunction (impaired vasodilation, prothrombotic, proinflammatory and prooxidant states) is involved in the development of cardiovascular diseases (atherosclerosis, hypertension, heart failure, stroke) and vascular complications of diabetes mellitus. Reduced production of endothelium-derived relaxing factors, increased release of endothelium-derived constricting factors, prothrombotic molecules and inflammatory mediators, upregulation of growth factors and adhesion molecules play a crucial role in the development and progression of endothelial dysfunction. Phytochemicals belonging to different chemical classes (alkaloids, flavonoids, isoflavonoids, phenolic acids, terpenoids) were reported to prevent and/or reverse endothelial dysfunction in different experimental models. Many of them showed a multitarget activity which is a great advantage in tackling endothelial dysfunction and thereby, they may serve as lead compounds for novel drug development. Salvianolic acid B, caffeic, chlorogenic, ferulic and rosmarinic acids, resveratrol, luteolin are only some examples of phytochemicals modulating multiple mechanisms associated with endothelial dysfunction. Obviously, extensive clinical trials are needed to confirm the efficacy of phytochemicals in improving endothelial function and also their safety. In addition, formulation strategies to enhance bioavailability and afford an endothelium-targeted delivery should be explored.

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Abbreviations

ACE:

Angiotensin I-converting enzyme

Ach:

Acetylcholine

ADMA:

Asymmetric dimethylarginine

AGEs:

Advanced glycation end products

Akt:

Protein kinase B

AMPK:

5′ Adenosine monophosphate activated protein kinase

Ang II:

Angiotensin II

AP-1:

Activator protein-1

ApoE−/− :

Apolipoprotein E gene knockout

ARE:

Antioxidant response element

ASS:

Arginine-succinate synthase

AT1:

Angiotensin II type 1 receptor

ATP:

Adenosine triphosphate

BAEC:

Bovine aortic endothelial cells

Bcl-2:

B cell lymphoma 2

BH4 :

Tetrahydrobiopterin

BMEC:

Brain microvascular endothelial cells

BMP4:

Bone morphogenetic protein 4

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

CHOP:

C/EBP homologous protein

CMEC:

Cardiac microvascular endothelial cells

cNOS:

Constitutive nitric oxide synthase

COX-2:

Cyclooxygenase-2

CRP:

C reactive protein

DDA:

Dimethylarginine dimethylaminohydrolase

DHFR:

Dihydrofolate reductase

DOCA:

Deoxycorticosterone acetate

DRP 1:

Dynamin-related protein 1

EA.hy926:

Transformed human umbilical vein cell line

eIf2α:

Eukaryotic initiation factor 2α

eNOS:

Endothelial nitric oxide synthase

ERK1/2:

Extracellular signal-regulated kinase 1/2

ET-1:

Endothelin-1

FIS 1:

Mitochondrial fission protein 1

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

glyLDL:

Glycated low-density lipoprotein

GPIIb/GPIIIa:

Glycoprotein IIb/IIIa

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GRP78/GRP94:

Glucose-regulated protein 78/94 kDa

GSH:

Glutathione

GSR:

Glutathione-disulfide reductase

GST:

Glutathione S-transferase

GTPCH-1:

Guanosine triphosphate cyclohydrolase 1

HAEC:

Human aortic endothelial cells

HBMEC:

Human brain microvascular endothelial cells

HIF-1α:

Hypoxia-inducible factor 1α

HMGB1:

High mobility group box 1 protein

HO-1:

Heme oxygenase-1

HREGC:

Human renal glomerulus endothelial cells

hsCRP:

High-sensitivity C reactive protein

HUVEC:

Human umbilical vein endothelial cells

i.p.:

Intraperitoneally

ICAM-1:

Intercellular adhesion molecule 1

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

JNK:

c-Jun N-terminal kinase

KLF2:

Krüppel-like Factor 2

LC3-I/II:

Light-chain 3-I/II

LOX-1:

Lectin-like oxidized low-density lipoprotein receptor-1

LPC:

Lysophosphatidylcholine

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

mBMEC:

Mouse primary brain microvascular endothelial cells

MCP-1:

Monocyte chemoattractant protein-1

MDA:

Malondialdehyde

MMP-9:

Matrix metalloproteinase-9

mRNA:

Messenger ribonucleic acid

mTOR:

Mammalian target of rapamycin

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NOX:

NADPH oxidase

Nrf2:

Nuclear factor erythroid 2-related factor 2

oxLDL:

Oxidized low-density lipoprotein

ox-sdLDL:

Oxidized small dense low-density lipoprotein

p62:

Protein 62

PAEC:

Pulmonary artery endothelial cells

PAI-1:

Plasminogen activator inhibitor-1

PARS:

Poly-ADP ribosyl synthetase

PDE:

Phosphodiesterase

PG:

Prostaglandin

PGI2 :

Prostacyclin (prostaglandin I2)

PI3K:

Phosphatidylinositol 3-kinase

PKCβII:

Protein kinase C βII

p-MLC:

Phosphorylated myosin light chain

PON-1:

Paraoxonase-1

PPARγ:

Peroxisome proliferator-activated receptor γ

PTX3:

Pentraxin 3

RAEC:

Rat aortic endothelial cells

RAGE:

Receptor for advanced glycation end-products

RNS:

Reactive nitrogen species

ROCK 1:

Rho-associated protein kinase 1

ROS:

Reactive oxygen species

s.c.:

Subcutaneous

SAA:

Serum amyloid A

sE-selectin:

Soluble E-selectin

SGLT:

Sodium-glucose linked transporter

SIRT1:

Sirtuin 1

SOD:

Superoxide dismutase

TAA:

Total antioxidant activity

TBARS:

Thiobarbituric acid reactive substances

TEER:

Transendothelial electrical resistance

TGF-α:

Transforming growth factor α

TIMP1:

Tissue inhibitor of metalloproteinase-1

TLR2/4:

Toll-like receptor-2/4

TM:

Thrombomodulin

TNF-α:

Tumor necrosis factor-α

t-PA:

Tissue plasminogen activator

TRPM8:

Transient receptor potential cation channel subfamily M member 8

TrxR:

Thioredoxin reductase

TXA2 :

Thromboxane A2

TXB2 :

Thromboxane B2

Txn1:

Thioredoxin 1

VASP:

Vasodilator-stimulated phosphoprotein

VCAM-1:

Vascular cell adhesion molecule 1

VEGF:

Vascular endothelial growth factor

vWF:

von Willebrand factor

XO-1:

Xanthine oxidase-1

ZO-1:

Zonula occludens

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Acknowledgements

Alexandra Bujor gratefully acknowledges the financial support of Grigore T. Popa University of Medicine and Pharmacy Iasi, Grant No. 7626/18.04.2019.

Funding

The present work was supported by Grant No. 7626/18.04.2019 from Grigore T. Popa University of Medicine and Pharmacy Iasi (Romania).

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115, Iasi, Romania

    Alexandra Bujor

  2. Department of Pharmacognosy, Faculty of Pharmacy, Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115, Iasi, Romania

    Anca Miron, Adriana Trifan, Simon Vlad Luca & Ana Clara Aprotosoaie

  3. Biothermodynamics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Maximus-von-Imhof-Forum 2, 85354, Freising, Germany

    Simon Vlad Luca

  4. National Institute of Research and Development for Biological Sciences Bucuresti/Stejarul Biological Research Centre, 6 Alexandru cel Bun Street, 610004, Piatra Neamt, Romania

    Elvira Gille

  5. Department of Biophysics and Medical Physics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115, Iasi, Romania

    Sorin-Dan Miron

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  1. Alexandra Bujor
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Bujor, A., Miron, A., Trifan, A. et al. Phytochemicals and endothelial dysfunction: recent advances and perspectives. Phytochem Rev 20, 653–691 (2021). https://doi.org/10.1007/s11101-020-09728-y

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