Alterations in vascular matrix metalloproteinase due to ageing and chronic hypertension: effects of endothelin receptor blockade.
OBJECTIVE
To determine the effects of age and dual endothelin (ET)A/ETB receptor antagonism (bosentan) on aortic matrix metalloproteinase (MMP) abundance and tissue inhibitor of metalloproteinase (TIMP) expression in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR).


METHODS
Male SHR and control WKY rats were randomly assigned to receive placebo or bosentan (100 mg/kg per day) for 3 months. Animals were killed under terminal anaesthesia at either 20 weeks (adult) or 17-20 months (senescent). Aortic gelatinase activity was determined by zymography, whereas MT-1 MMP and TIMP-1 expression were assessed by immunoblotting.


RESULTS
In WKY rats, aortic MMP-2 but not proMMP-2 activity was 3.6-fold higher (P < 0.02) in the senescent compared with the adult group. TIMP-1 (twofold) and MT-1 MMP (3.8-fold) expression increased (P < 0.05) with age in the WKY groups. Short-term hypertension (adult SHR versus adult WKY) increased MMP-2 to 74.7 +/- 14.1 from 18.9 +/- 3.5 arbitrary units (AU) (P = 0.0012), but did not alter proMMP-2 activity. This increased further on progression to chronic hypertension (117.4 +/- 12.2 versus 74.7 +/- 14.1 AU; P < 0.02). Bosentan decreased MMP-2 (78.9 +/- 3.8 versus 117.4 +/- 12.2 AU; P = 0.014) and proMMP-2 activity (P < 0.006) in the senescent SHR group.


CONCLUSIONS
Ageing and the development/progression of hypertension are associated with increased MMP-2 activity in the aorta, which is consistent with ongoing remodelling of the vasculature. However, the underlying mechanisms regulating MMP-2 abundance in ageing and hypertension appear to be divergent, as MT-1 MMP expression is differentially altered. Dual ETA/ETB receptor antagonism did not alter the age-dependent increase in aortic MMP activity in normotensive rats. However, bosentan decreased pro and active MMP-2 activity in senescent SHR rats, indicating that ET modulates late events in vascular remodelling in hypertension.
Spiers
James P
JP
Department of Pharmacology and Therapeutics, Trinity Centre for Health Sciences, Trinity College Dublin, St. James's Hospital, James's Street, Dublin 8, Ireland. spiersj@tcd.ie
Kelso
Elizabeth J
EJ
Siah
Wei F
WF
Edge
Gillian
G
Song
Guojie
G
McDermott
Barbara J
BJ
Hennessy
Martina
M
D000375:Aging; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000201:enzymology; D015153:Blotting, Western; D000077300:Bosentan; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000201:enzymology; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D012015:Reference Standards; D013449:Sulfonamides / Q000494:pharmacology
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D004792:Enzyme Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; D000077300:Bosentan