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Sodium-Glucose Cotransporter-2 Inhibitors in Vascular Biology: Cellular and Molecular Mechanisms

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Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new antidiabetic drugs that reduce hyperglycemia by inhibiting the glucose reabsorption in renal proximal tubules. Clinical studies have shown that SGLT2 inhibitors not only improve glycemic control but also reduce major adverse cardiovascular events (MACE, cardiovascular and total mortality, fatal or nonfatal myocardial infarction or stroke) and hospitalization for heart failure (HF), and improve outcome in chronic kidney disease. These cardiovascular and renal benefits have now been confirmed in both diabetes and non-diabetes patients. The precise mechanism(s) responsible for the protective effects are under intensive investigation. This review examines current evidence on the cardiovascular benefits of SGLT2 inhibitors, with a special emphasis on the vascular actions and their potential mechanisms.

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Abbreviations

AAA:

Abdominal aortic aneurysm

AGE:

Advanced glycation end-product

AIx:

Augmentation index

AMBP:

Ambulatory blood pressure

CVD:

Cardiovascular disease

EC:

Endothelial cell

EDR:

Endothelium-dependent relaxation

EiPH:

Exercise-induced pulmonary hypertension

ESRD:

End-stage renal disease

FMD:

Flow-mediated dilation

GPx:

Glutathione peroxidase

HbA1c:

Hemoglobin A1c

HF:

Heart failure

HFrEF:

Heart failure with reduced ejection fraction

HLI:

Hind-limb ischemia

HO-1:

Heme oxygenase-1

hsCRP:

High-sensitivity C-reactive protein

ICAM-1:

Intercellular adhesion molecule-1

IMT:

Intima-media thickness

MMP7:

Matrix metalloproteinase 7

NHE:

Na+/H+ exchanger

NLRP3:

Nucleotide-binding oligomerization domain (NOD)-like receptor 3

NOX:

NADPH oxidase

NRF2:

NF-E2-related factor-2

PAH:

Pulmonary arterial hypertension

PAR:

Proteinase-activated receptor

PCT:

Proximal convoluted tubules

PDGF:

Platelet-derived growth factor

PVAT:

Perivascular adipose tissue

PWV:

Pulse wave velocity

SGLT2:

Sodium-glucose cotransporter-2

SHR:

Spontaneously hypertensive rat

SNP:

Sodium nitroprusside

SOD:

Superoxide dismutase

T2DM:

Type 2 diabetes mellitus

UA:

Uric acid

VCAM-1:

Vascular adhesion molecule-1

VSMC:

Vascular smooth muscle cell

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Acknowledgments

We apologize for omitting many worthy references due to space limitations.

Funding

Grant support was received from the Ministry of Science and Technology (National Key R&D Program 2018YFA0800600) and the National Science Foundation of China (91939108, 81830015 and 81770497).

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  1. Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, 710061, China

    Lei Xiao

  2. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Xin Nie & Yanyan Cheng

  3. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, 100191, China

    Nanping Wang

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  1. Lei Xiao
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L.X., X.N., Y.C and N.W. drafted the manuscript; N.W. edited and revised the manuscript; L.X., X.N., Y.C and N.W. approved the final version of the manuscript.

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Xiao, L., Nie, X., Cheng, Y. et al. Sodium-Glucose Cotransporter-2 Inhibitors in Vascular Biology: Cellular and Molecular Mechanisms. Cardiovasc Drugs Ther 35, 1253–1267 (2021). https://doi.org/10.1007/s10557-021-07216-9

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