title: Significance of AT1 receptor independent activation of mineralocorticoid receptor in murine diabetic cardiomyopathy.
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).
  
  
  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 KO-DM, 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. AT1-independent MR activation in the LV might be responsible for the pathogenesis of diabetic cardiomyopathy.
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagatomo
authors.affiliation: Department of Cardiology, KAKEN Hospital, International University of Health and Welfare, Ichikawa, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Meguro
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kimi
authors.initials: K
authors.lastname: Koide
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077545:Eplerenone; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone