Cardiac remodeling after long term norepinephrine treatment in rats.
OBJECTIVE
In this study we have tested the hypothesis that degradation of collagen by matrix metalloproteinase 2 (MMP-2) precedes the deposition of extracellular matrix (ECM) after long term norepinephrine (NE) treatment.


METHODS
Female Sprague-Dawley rats received continuous i.v. infusion of NE (0.1 mg/kg.h) for 1, 2, 3, 4 and 14 days. Heart function and weight as well as expression of cardiac colligin and of collagen I and III were examined. Furthermore, we have assessed the degradation pathway of collagen by measuring the mRNA and activity of myocardial MMP-2 and tissue inhibitor of metalloproteinase 2 (TIMP-2) as well as the protein level of TIMP-2.


RESULTS
NE induced hypertrophy predominantly of the left ventricle (LV) in a time-dependent manner. It increased the mRNAs of colligin, collagen I and III, and of MMP-2 and TIMP-2 as well as MMP-2 activity in two phases: In the initial phase, at 3 and 4 days, the mRNA of colligin and of collagen I and III was elevated predominantly in the LV, MMP-2 and TIMP-2 mRNA, as well as TIMP-2 protein and MMP-activity were increased in both ventricles. The second phase, after 14 days, was characterized by a less pronounced increase in colligin, collagen I and III and in MMP-2 activity which occurred exclusively in the LV. Finally, long-term treatment with NE induced a 37% increase in interstitial fibrosis which was shown to occur exclusively in the LV after 14 days.


CONCLUSIONS
NE treatment induced fibrosis exclusively in the LV which was associated with hypertrophy predominantly of the LV. The elevated MMP-2 activity seems to be necessary for the ECM to adapt to the enlargement of myocytes and to reduce overproduction of collagen.
Briest
W
W
Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstr. 27, D-04103, Leipzig, Germany. barw@medizin.uni-leipzig.de
Hölzl
A
A
Rassler
B
B
Deten
A
A
Leicht
M
M
Baba
H A
HA
Zimmer
H G
HG
D018674:Adrenergic Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology; D007262:Infusions, Intravenous; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D015737:Nisoldipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling
D018674:Adrenergic Antagonists; D002121:Calcium Channel Blockers; D002227:Carbazoles; D024042:Collagen Type I; D024061:Collagen Type III; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; D019716:Tissue Inhibitor of Metalloproteinase-2; D015737:Nisoldipine; D020778:Matrix Metalloproteinase 2; D009638:Norepinephrine