Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts.
OBJECTIVE
Norepinephrine (NE) induced hypertrophy and remodelling of the extracellular matrix (ECM) in the left ventricle (LV) of the rat heart with resulting fibrosis. However, there was no increased collagen deposition in the right ventricle (RV). To test the hypothesis that lack of RV fibrosis is the result of elevated cleavage of collagens we inhibited the activity of matrix metalloproteinases (MMP) by doxycycline (Doxy) and then measured function and collagen metabolism in the RV as compared to the LV.


METHODS
Female Sprague-Dawley rats were treated with 30 mg/kg per day doxycycline alone or in combination with i.v. infusion of NE (0.1 mg/kg per h). The activity of MMP-2 was increased both in the LV and RV after 3 days of NE infusion and reduced after concomitant doxycycline treatment which also caused inhibition when given alone.


RESULTS
After 14 days of NE infusion in combination with doxycycline there was an additional increase in the NE-induced elevation of collagen accumulation in the LV (interstitial collagen fraction: NE-Doxy 1.797%, P<0.05 versus control and NE; NE 1.113%, P<0.05 versus control) and significant fibrosis in the RV (2.105%, P<0.05 versus control). This correlated with the prevention of the NE-induced elevation of RV systolic pressure (NE: 71.3 mmHg, P<0.05; NE-Doxy: 36.4 mmHg) and RV dP/dt(max) (NE: 5500 mmHg/s, P<0.05; NE-Doxy: 2550 mmHg/s). Also in the NE-stimulated LV, the doxycycline-induced collagen accumulation was associated with reduced LV dP/dt(max) (NE-Doxy: 13169 mmHg/s; NE: 18849 mmHg/s, P<0.05).


CONCLUSIONS
MMP inhibition leads to myocardial stiffness with negative functional consequences for the RV and LV in NE-treated rat hearts.
Briest
Wilfried
W
Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstrasse 27, D-04103 Leipzig, Germany. briestw@medizin.uni-leipzig.de
Hölzl
Alexander
A
Rassler
Beate
B
Deten
Alexander
A
Baba
Hideo A
HA
Zimmer
Heinz-Gerd
HG
D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000201:enzymology / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D004318:Doxycycline; D009638:Norepinephrine