Document Detail


Mapping genetic determinants of coronary microvascular remodeling in the spontaneously hypertensive rat.
MedLine Citation:
PMID:  23197152     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5%]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR <5%), but not with blood pressure indices, were prioritized and four candidate genes were identified (Rtel1, Pla2g5, Dnaja4 and Rcn2) according to their expression levels and biological functions. Our results demonstrate that genetic factors play a role in the development of coronary microvascular remodeling and suggest blood pressure independent candidate genes for further functional experiments.
Authors:
Massimiliano Mancini; Enrico Petretto; Christina Kleinert; Angela Scavone; Tisham De; Stuart Cook; Jan Silhavy; Vaclav Zidek; Michal Pravenec; Giulia d'Amati; Paolo G Camici
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-30
Journal Detail:
Title:  Basic research in cardiology     Volume:  108     ISSN:  1435-1803     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-11-30     Completed Date:  2013-08-05     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  316     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure
Coronary Vessels / pathology*,  physiopathology
Genome-Wide Association Study
Hypertension / genetics,  pathology*,  physiopathology
Male
Microvessels / pathology,  physiopathology
Myocardium / metabolism
Quantitative Trait Loci*
Rats
Rats, Inbred BN
Rats, Inbred SHR
Rats, Inbred WKY
Grant Support
ID/Acronym/Agency:
FS/11/25/28740//British Heart Foundation; MC_U120097112//Medical Research Council

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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