Document Detail


Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via "nongenomic effects".
MedLine Citation:
PMID:  20625113     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-beta hydroxysteroid dehydrogenase, salt-mineralocorticoid-induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction.
METHODS AND RESULTS: Cardiac structure and function, oxidative stress, and mineralocorticoid receptor-dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor-dependent gene transcription.
CONCLUSIONS: Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor-dependent gene transcription.
Authors:
Selma F Mohammed; Tomohito Ohtani; Josef Korinek; Carolyn S P Lam; Katarina Larsen; Robert D Simari; Maria L Valencik; John C Burnett; Margaret M Redfield
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-07-12
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-27     Completed Date:  2010-09-13     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  370-8     Citation Subset:  AIM; IM    
Affiliation:
Cardiovascular Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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MeSH Terms
Descriptor/Qualifier:
Aldosterone / adverse effects
Animals
Atrial Natriuretic Factor / genetics
Capillaries / pathology
Collagen / genetics
Cytochrome b Group / genetics
Desoxycorticosterone / pharmacology
Heart Failure / chemically induced*,  pathology,  physiopathology
Inflammation / pathology,  physiopathology
Male
Membrane Glycoproteins / genetics
Mice
Mice, Inbred Strains
Mineralocorticoids / adverse effects*
NADPH Oxidase / genetics
Osteopontin / genetics
Oxidative Stress / physiology
RNA / genetics,  isolation & purification
RNA, Messenger / genetics
Reverse Transcriptase Polymerase Chain Reaction
Stroke Volume / drug effects,  physiology*
Ventricular Function, Left / drug effects,  physiology
Grant Support
ID/Acronym/Agency:
1 UL1 RR024150/RR/NCRR NIH HHS; HL-07111/HL/NHLBI NIH HHS; HL-63281/HL/NHLBI NIH HHS; HL-76611-1/HL/NHLBI NIH HHS; P01 HL076611-05/HL/NHLBI NIH HHS; R01 HL063281-08/HL/NHLBI NIH HHS; T32 HL007111-35/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cytochrome b Group; 0/Membrane Glycoproteins; 0/Mineralocorticoids; 0/RNA, Messenger; 106441-73-0/Osteopontin; 52-39-1/Aldosterone; 63231-63-0/RNA; 64-85-7/Desoxycorticosterone; 85637-73-6/Atrial Natriuretic Factor; 9007-34-5/Collagen; EC 1.6.-/Nox4 protein, mouse; EC 1.6.3.1/Cybb protein, mouse; EC 1.6.3.1/NADPH Oxidase; EC 1.6.3.1/p22(phox) protein, mouse
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