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. CONCLUSION: 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.
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 hypertensiverats (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. CONCLUSION: 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.
Authors: Mingyi Wang; Jing Zhang; Richard Telljohann; Liqun Jiang; James Wu; Robert E Monticone; Kapil Kapoor; Mark Talan; Edward G Lakatta Journal: Hypertension Date: 2012-06-11 Impact factor: 10.190
Authors: Ayush Batra; Lawrence L Latour; Christl A Ruetzler; John M Hallenbeck; Maria Spatz; Steven Warach; Erica C Henning Journal: J Cereb Blood Flow Metab Date: 2010-03-03 Impact factor: 6.200
Authors: Amie K Lund; JoAnn Lucero; Selitá Lucas; Michael C Madden; Jacob D McDonald; Jean-Clare Seagrave; Travis L Knuckles; Matthew J Campen Journal: Arterioscler Thromb Vasc Biol Date: 2009-01-15 Impact factor: 8.311