Microarray identifies extensive downregulation of noncollagen extracellular matrix and profibrotic growth factor genes in chronic isolated mitral regurgitation in the dog.
BACKGROUND
The volume overload of isolated mitral regurgitation (MR) in the dog results in left ventricular (LV) dilatation and interstitial collagen loss. To better understand the mechanism of collagen loss, we performed a gene array and overlaid regulated genes into ingenuity pathway analysis.


RESULTS
Gene arrays from LV tissue were compared in 4 dogs before and 4 months after MR. Cine-magnetic resonance-derived LV end-diastolic volume increased 2-fold (P=0.005), and LV ejection fraction increased from 41% to 53% (P<0.007). LV interstitial collagen decreased 40% (P<0.05) compared with controls, and replacement collagen was in short strands and in disarray. Ingenuity pathway analysis identified Marfan syndrome, aneurysm formation, LV dilatation, and myocardial infarction, all of which have extracellular matrix protein defects and/or degradation. Matrix metalloproteinase-1 and -9 mRNA increased 5- (P=0.01) and 10-fold (P=0.003), whereas collagen I did not change and collagen III mRNA increased 1.5-fold (P=0.02). However, noncollagen genes important in extracellular matrix structure were significantly downregulated, including decorin, fibulin 1, and fibrillin 1. In addition, connective tissue growth factor and plasminogen activator inhibitor were downregulated, along with multiple genes in the transforming growth factor-beta signaling pathway, resulting in decreased LV transforming growth factor-beta1 activity (P=0.03).


CONCLUSIONS
LV collagen loss in isolated, compensated MR is chiefly due to posttranslational processing and degradation. The downregulation of multiple noncollagen genes important in global extracellular matrix structure, coupled with decreased expression of multiple profibrotic factors, explains the failure to replace interstitial collagen in the MR heart.
Zheng
Junying
J
Center for Heart Failure Research, Division of Cardiology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, USA.
Chen
Yuanwen
Y
Pat
Betty
B
Dell'italia
Louis A
LA
Tillson
Michael
M
Dillon
A Ray
AR
Powell
Pamela C
PC
Shi
Ke
K
Shah
Neil
N
Denney
Thomas
T
Husain
Ahsan
A
Dell'Italia
Louis J
LJ
D000818:Animals; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D058575:Decorin; D004285:Dogs; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D039564:Integrin alphaV / Q000096:biosynthesis / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008944:Mitral Valve Insufficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D013318:Stroke Volume; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
D058575:Decorin; D016326:Extracellular Matrix Proteins; D039564:Integrin alphaV; D011509:Proteoglycans; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D003094:Collagen