Document Detail


Adenylyl cyclase 6 deletion reduces left ventricular hypertrophy, dilation, dysfunction, and fibrosis in pressure-overloaded female mice.
MedLine Citation:
PMID:  20359598     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: This study sought to test the hypothesis that pressure stress of the adenylyl cyclase 6-deleted (AC6-KO) heart would result in excessive hypertrophy, early dilation and dysfunction, and increased fibrosis.
BACKGROUND: Cardiac-directed AC6 expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy.
METHODS: AC6-KO and control (CON) mice underwent transverse aortic constriction (TAC) to induce pressure overload. Measures of LV hypertrophy, function, and fibrosis were obtained 3 weeks after TAC, and LV samples were assessed for alterations in expression of FHL1 and periostin.
RESULTS: Three weeks after TAC, female AC6-KO mice had preserved left ventricular (LV) ejection fraction (CON: 22+/-2%; AC6-KO: 52+/-4%; p<0.001) and reduced LV end-diastolic dimension (CON: 4.6+/-0.1 mm; AC6-KO: 3.6+/-0.1 mm; p<0.001). Reduced LV/tibial length ratio (CON: 10.4+/-1.5 mg/mm; AC6-KO: 7.5+/-2.3 mg/mm; p<0.001) and reduced LV expression of atrial natriuretic factor (p<0.05), alpha-skeletal muscle actin (p<0.05), and beta-myosin heavy chain (p<0.05) were observed in AC6-KO mice. In addition, AC6 deletion was associated with less LV fibrosis (p<0.01) and reduced collagen types I (p<0.05) and III (p<0.05) expression 3 weeks after TAC. LV protein expression of FHL1 (p<0.02) and periostin (p=0.04) were reduced after TAC in AC6-KO mice. The roles of AC6 deletion in cardiac myocytes and fibroblasts were examined in vitro using pharmacological hypertrophy and AC6 knockdown (small interfering ribonucleic acid), which recapitulated in vivo findings.
CONCLUSIONS: The deleterious effects of LV pressure overload were reduced in female mice with AC6 deletion. Reductions in FHL1 and periostin expression, direct consequences of reduced AC6 in cardiac myocytes and fibroblasts, appear to be of mechanistic importance for these unanticipated beneficial effects.
Authors:
Tong Tang; N Chin Lai; H Kirk Hammond; David M Roth; Yuan Yang; Tracy Guo; Mei Hua Gao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  55     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-02     Completed Date:  2010-06-01     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1476-86     Citation Subset:  AIM; IM    
Copyright Information:
Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adenylate Cyclase / genetics*
Animals
Cell Adhesion Molecules / genetics
Female
Hypertrophy, Left Ventricular / genetics*
Intracellular Signaling Peptides and Proteins
LIM Domain Proteins
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle Proteins / genetics
Sequence Deletion
Ventricular Dysfunction, Left / genetics*
Grant Support
ID/Acronym/Agency:
HL081741/HL/NHLBI NIH HHS; HL088426/HL/NHLBI NIH HHS; P01 HL066941/HL/NHLBI NIH HHS; P01 HL066941-10/HL/NHLBI NIH HHS; P01HL066941/HL/NHLBI NIH HHS; R01 HL081741/HL/NHLBI NIH HHS; R01 HL081741-07/HL/NHLBI NIH HHS; R01 HL088426/HL/NHLBI NIH HHS; R01 HL088426-03/HL/NHLBI NIH HHS; R01 HL088426-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Fhl1 protein, mouse; 0/Intracellular Signaling Peptides and Proteins; 0/LIM Domain Proteins; 0/Muscle Proteins; 0/Postn protein, mouse; EC 4.6.1.1/Adenylate Cyclase; EC 4.6.1.1/adenylyl cyclase 6
Comments/Corrections

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