Alterations in vascular matrix metalloproteinase due to ageing and chronic hypertension : effects of endothelin receptor blockade

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). Male SHR and contr...

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Published in:	Journal of hypertension Vol. 23; no. 9; pp. 1717 - 1724
Main Authors:	SPIERS, James P, KELSO, Elizabeth J, SIAH, Wei F, EDGE, Gillian, GUOJIE SONG, MCDERMOTT, Barbara J, HENNESSY, Martina
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 01-09-2005
Subjects:	Aging Animals Antihypertensive agents Antihypertensive Agents - pharmacology Aorta, Thoracic - enzymology Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Blotting, Western Bosentan Cardiology. Vascular system Cardiovascular system Clinical manifestations. Epidemiology. Investigative techniques. Etiology Endothelin A Receptor Antagonists Endothelin B Receptor Antagonists Endothelin Receptor Antagonists Endothelium, Vascular - enzymology Enzyme Precursors - metabolism Gelatinases - metabolism Hypertension - metabolism Male Matrix Metalloproteinase 2 - metabolism Matrix Metalloproteinases - metabolism Medical sciences Metalloendopeptidases - metabolism Microscopy, Fluorescence Pharmacology. Drug treatments Rats Rats, Inbred SHR Rats, Inbred WKY Receptor, Endothelin A - genetics Receptor, Endothelin A - metabolism Receptor, Endothelin B - genetics Receptor, Endothelin B - metabolism Receptors, Endothelin - genetics Receptors, Endothelin - metabolism Reference Standards Sulfonamides - pharmacology Hypertension endothelin antagonist Endothelin Ageing Aorta Cardiovascular disease matrix metalloproteinase
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Summary:	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). 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0263-6352 1473-5598
DOI:	10.1097/01.hjh.0000176787.04753.ee