Matrix metalloproteinases contribute to endotoxin and interleukin-1beta induced vascular dysfunction.
OBJECTIVE
The acute vascular inflammatory dysfunction associated with endotoxaemia may reflect an imbalance between matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs), induced by the endotoxin. This possibility was tested in rat aortic tissue.


METHODS
Tone induced by phenylephrine in aortic rings was measured after exposure in vitro to ambient lipopolysaccharide (LPS) or the proinflammatory cytokine interleukin-1beta (IL-1beta) for 6h, with or without MMP inhibitors (doxycycline or GM6001). Gelatinase and MMP activities, TIMP proteins and contractility were measured in aortae taken from rats 6h after receiving LPS in vivo.


RESULTS
Inhibition of MMP prevented the loss of phenylephrine-induced tone in aortic rings after LPS or IL-1beta. IL-1beta also increased release of MMP-2 activity from aortic tissue. In aortae exposed in vivo to LPS, net gelatinase, MMP-9 activities and TIMP-1 protein levels were increased, whereas TIMP-4 was reduced. These aortae were hypocontractile to both phenylephrine and KCl. Hypocontractility was partially reversed by doxycycline ex vivo.


CONCLUSIONS
MMP inhibitors ameliorate vascular hyporeactivity induced by either LPS or IL-1beta in vitro. LPS in vivo alters the balance between MMPs and TIMPs, contributing to vascular dysfunction which is partially reversed by MMP inhibitors. Vascular MMPs are activated as a result of LPS or IL-1beta-induced stress and contribute to the hyporeactivity of blood vessels to vasoconstrictors.
Lalu
M M
MM
Department of Pharmacology, Cardiovascular Research Group, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada.
Cena
J
J
Chowdhury
R
R
Lam
A
A
Schulz
R
R
D000818:Animals; D001013:Aorta, Thoracic; D015153:Blotting, Western; D017364:Collagenases / Q000378:metabolism; D019446:Endotoxemia / Q000201:enzymology*; D004731:Endotoxins / Q000097:blood / Q000633:toxicity*; D018093:Gelatinases / Q000378:metabolism; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000633:toxicity*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced* / Q000201:enzymology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000097792:Tissue Inhibitor of Metalloproteinase-4
D017364:Collagenases; D004731:Endotoxins; D018093:Gelatinases; D007375:Interleukin-1; D020782:Matrix Metalloproteinases; D009124:Muscle Proteins; D009566:Nitrates; D009573:Nitrites; D010656:Phenylephrine; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D014662:Vasoconstrictor Agents; D000097792:Tissue Inhibitor of Metalloproteinase-4