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Br J Pharmacol. 2015 Oct;172(19):4684-98. doi: 10.1111/bph.13242. Epub 2015 Aug 10.

Tissue-specific up-regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus.

Author information

1
Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
2
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.

Abstract

BACKGROUND AND PURPOSE:

Emerging evidence suggests a selective up-regulation of arginase I in diabetes causing coronary artery disease; however, the mechanisms behind this up-regulation are still unknown. Activated p38 MAPK has been reported to increase arginase II in various cardiovascular diseases. We therefore tested the role of p38 MAPK in the regulation of arginase I and II expression and its effect on endothelial dysfunction in diabetes mellitus.

EXPERIMENTAL APPROACH:

Endothelial function was determined in septal coronary (SCA), left anterior descending coronary (LAD) and mesenteric (MA) arteries from healthy and streptozotocin-induced diabetic Wistar rats by wire myographs. Arginase activity and protein levels of arginase I, II, phospho-p38 MAPK and phospho-endothelial NOS (eNOS) (Ser(1177) ) were determined in these arteries from diabetic and healthy rats treated with a p38 MAPK inhibitor in vivo.

KEY RESULTS:

Diabetic SCA and MA displayed impaired endothelium-dependent relaxation, which was prevented by arginase and p38 MAPK inhibition while LAD relaxation was not affected. Arginase I, phospho-p38 MAPK and eNOS protein expression was increased in diabetic coronary arteries. In diabetic MA, however, increased expression of arginase II and phospho-p38 MAPK, increased arginase activity and decreased expression of eNOS were observed. All these effects were reversed by p38 MAPK inhibition.

CONCLUSIONS AND IMPLICATIONS:

Diabetes-induced activation of p38 MAPK causes endothelial dysfunction via selective up-regulation of arginase I expression in coronary arteries and arginase II expression in MA. Therefore, regional differences appear to exist in the arginase isoforms contributing to endothelial dysfunction in type 1 diabetes mellitus.

PMID:
26140333
PMCID:
PMC4594272
DOI:
10.1111/bph.13242
[Indexed for MEDLINE]
Free PMC Article

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