Cardiac remodeling in erythropoietin-transgenic mice.
BACKGROUND
Transgenic (tg) mice with chronic overexpression of the human erythropoietin gene are characterized by an increased hematocrit of about 0.80 in adulthood. This is accompanied by cardiac dysfunction and premature death. The aim of this study was to examine whether this cardiac dysfunction was accompanied by hypertrophy of the heart with remodeling of the extracellular matrix (ECM).


METHODS
3-months-old wild type (wt) and tg mice without cardiac hypertrophy were compared with the respective 7-months-old mice. The mRNA of brain natriuretic peptide (BNP), of the matrix metalloproteinases (MMP)-2, -8, -9, -13, of the tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, -4 and of collagen I and III was detected by ribonuclease protection assay. The activity of MMPs was measured by zymography.


RESULTS
There was hypertrophy of both ventricles in 7-months-old tg mice, which was accompanied by elevated mRNA expression of BNP. MMP-2 activity was increased and MMP-9 activity was decreased in the left ventricle (LV) of 3-months-old tg mice. This was accompanied by elevated TIMP-4 expression, followed by a shift of collagen mRNA expression from type III to type I in this ventricle.


CONCLUSIONS
The shift to collagen I in the heart of tg mice might be associated with a stiffer ventricle resulting in diastolic dysfunction. This may be responsible for a relative and intermittent LV- and right ventricle (RV)-insufficiency which was likely to have occurred as evidenced by the elevation of lung and liver weight with hemorrhage and interstitial fibrosis after 7 months.
Briest
Wilfried
W
Carl-Ludwig-Institute of Physiology, University of Leipzig, Germany. briestw@medizin.uni-leipzig.de
Homagk
Lars
L
Baba
Hideo A
HA
Deten
Alexander
A
Rassler
Beate
B
Tannapfel
Andrea
A
Wagner
Klaus F
KF
Wenger
Roland H
RH
Zimmer
Heinz-Gerd
HG
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004921:Erythropoietin / Q000235:genetics* / Q000502:physiology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000097792:Tissue Inhibitor of Metalloproteinase-4
D003094:Collagen; D004921:Erythropoietin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D020097:Natriuretic Peptide, Brain; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4