Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure.
Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.
Qin
Wenning
W
Department of Genomics Sciences, Pfizer, Inc, St Louis, Mo 63167, USA.
Rudolph
Amy E
AE
Bond
Brian R
BR
Rocha
Ricardo
R
Blomme
Eric A G
EA
Goellner
Joseph J
JJ
Funder
John W
JW
McMahon
Ellen G
EG
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D000077545:Eplerenone; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control
D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2