ET(A)-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat.
Endothelin (ET) A (ET(A)) receptors activate matrix metalloproteinases (MMP). Since endothelin-1 (ET) is increased in myocardium late postmyocardial infarction (MI), we hypothesized that stimulation of ET(A) receptors contributes to activation of myocardial MMPs late post-MI. Three days post-MI, rats were randomized to treatment with the ET(A)-selective receptor antagonist sitaxsentan (n = 12) or a control group (n = 12). Six weeks later, there were rightward shifts of the left ventricular (LV) end-diastolic and end-systolic pressure-volume relationships, as measured ex vivo by the isovolumic Langendorff technique. Both shifts were markedly attenuated by sitaxsentan. In LV myocardium remote from the infarct, the activities of MMP-1, MMP-2, and MMP-9 were increased in the post-MI group, and the increases were prevented by sitaxsentan treatment. Expression of tissue inhibitor of MMP-1 was decreased post-MI, and the decrease was prevented by sitaxsentan treatment. Chronic post-MI remodeling is associated with activation of MMPs in myocardium remote from the infarct. Inhibition of ET(A) receptors prevents MMP activation and LV dilation, suggesting that ET, acting via the ET(A) receptor, contributes to chronic post-MI remodeling by its effects on MMP activity.
Podesser
B K
BK
Cardiovascular Section, Boston University Medical Center, and Myocardial Biology Unit and Cardiac Muscle Research Laboratory, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Siwik
D A
DA
Eberli
F R
FR
Sam
F
F
Ngoy
S
S
Lambert
J
J
Ngo
K
K
Apstein
C S
CS
Colucci
W S
WS
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure; D000252:Calcium-Transporting ATPases / Q000235:genetics; D065128:Endothelin Receptor Antagonists; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006339:Heart Rate; D006909:Hydroxyproline / Q000032:analysis; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000401:mortality; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D012492:Salts / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015996:Survival Rate; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D012492:Salts; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D009320:Atrial Natriuretic Factor; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D006909:Hydroxyproline