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Toxicology. 2019 Jul 1;423:105-111. doi: 10.1016/j.tox.2019.05.016. Epub 2019 May 31.

l-arginine alleviates doxorubicin-induced endothelium-dependent dysfunction by promoting nitric oxide generation and inhibiting apoptosis.

Author information

1
Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
2
Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
3
Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
4
Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address: liuyang19831119@163.com.
5
Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address: yangxl1012@yeah.net.

Abstract

BACKGROUND/AIMS:

Patients with doxorubicin (Dox) treatment have a high risk of developing vascular toxicity with an unknown mechanism. l-arginine is a substrate for nitric oxide (NO). The decreased level of arginine-NO metabolite in Dox-treated cancer patients was associated with increased level of vascular damage, which promoted us to investigate the mechanism of Dox-induced vascular dysfunction and verify whether l-arginine supplement could alleviate this vasculotoxic effect.

METHOD:

Within a mouse model of Dox injection (5 mg/kg i.p., 2 or 4 weeks), we measured vascular relaxation, blood pressure, vascular NO generation, apoptosis, and oxidative stress. We tested the efficacy of l-arginine (1.5 mg/g/day, 4 weeks) on Dox-induced vascular relaxation, blood pressure, vascular NO generation, apoptosis, as well as oxidative stress.

RESULTS:

Dox induced endothelium-dependent vascular dysfunction, which was associated with increased reactive oxidative stress (ROS) production and reduced NO generation in the vessel. ROS was required for Dox-induced apoptosis of both smooth muscle cells and endothelial cells. Dox treatment in mice increased blood pressure, but had no effect on vascular inflammation and fibrosis. L-aringine restored Dox-induced vascular dysfunction via enhancing vascular NO production and alleviating ROS-mediated apoptosis.

CONCLUSION:

We for the first time demonstrated l-arginine was effectively in suppressing Dox-induced vascular dysfunction, by attenuating vascular NO release and apoptosis. Our results provide a therapeutic target or a circulating marker for assessing vascular dysfunction which response to Dox treatment, and advance our understanding of the mechanisms of Dox-induced vascular dysfunction.

KEYWORDS:

Apoptosis; Doxorubicin; Reactive oxygen species; Vascular toxicity; l-arginine

PMID:
31158416
DOI:
10.1016/j.tox.2019.05.016

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