Significance of AT1 receptor independent activation of mineralocorticoid receptor in murine diabetic cardiomyopathy

Yuji Nagatomo, Tomomi Meguro, Hiroyuki Ito, Kimi Koide, Toshihisa Anzai, Keiichi Fukuda, Satoshi Ogawa, Tsutomu Yoshikawa

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Diabetes mellitus (DM) has deleterious influence on cardiac performance independent of coronary artery disease and hypertension. The objective of the present study was to investigate the role of the renin-angiotensin-aldosterone system, especially angiotensin II type 1a receptor (AT1aR) and mineralocorticoid receptor (MR) signaling, in left ventricular (LV) dysfunction induced by diabetes mellitus (DM). Methods and Results: DM was induced by intraperitoneal injection of streptozotocin (200 mg/kg BW) in wild-type (WT) or AT1aR knockout (KO) male mice, and they were bred during 6 or 12 weeks. Some KO mice were administered the MR antagonist eplerenone (100 mg/kg body weight). At 6 weeks, LV diastolic function was impaired in WT-DM, but preserved in KO-DM. At that time point MR mRNA expression was upregulated, NADPH oxidase subunit (p47phox) and glutathione peroxidase (GPx1) mRNA expression were upregulated, the staining intensities of LV tissue for 4-hydroxy-2-nonenal was stronger in immunohistochemistry, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells was increased, Bcl-2 protein expression was significantly downregulated, and the expression of SERCA2a and phosphorylated phospholamban was depressed in WT-DM, while these changes were not seen in KO-DM. At 12 weeks, however, these changes were also noted in KO-DM. Eplerenone arrested those changes. The plasma aldosterone concentration was elevated in WT-DM but not in KO-DM at 6 weeks. It showed 3.7-fold elevation at 12 weeks even in KODM, which suggests "aldosterone breakthrough" phenomenon. However, the aldosterone content in LV tissue was unchanged in KO-DM. Conclusions: DM induced diastolic dysfunction was observed even in KO at 12 weeks, which was ameliorated by minelarocorticoid receptor antagonist, eplerenone. AT 1-independent MR activation in the LV might be responsible for the pathogenesis of diabetic cardiomyopathy.

Original languageEnglish
Article numbere93145
JournalPloS one
Volume9
Issue number3
DOIs
Publication statusPublished - 2014 Mar 24

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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