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The role of endothelin in immune-mediated vascular injury

[Speaker] Neeraj Dhaun (Bean):1
1:Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

Hypertension is common and in the majority of cases its cause remains unknown. Recent interest has focused on the role of macrophages (M Φ) in blood pressure (BP) regulation. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor mediating its effects through two receptors - the endothelin-A receptor (ETA) and endothelin-B (ETB) receptor. The ET B receptor has a specific role in ET-1 clearance. We investigated the role of the M Φ ETB receptor in a model of angiotensin II (Ang II)-mediated end-organ damage.
MΦ ETB receptor deficient mice (LysMETB-/-) and controls were exposed to Ang II infusion for 6 weeks under a high salt diet. We assessed BP via telemetry, cardiac structure and function and endothelial function by Doppler ultrasound, end-organ injury and plasma and urine ET-1.
At baseline, components of BP did not differ between groups and increased similarly with Ang II. Whereas after 6 weeks of Ang II LysMETB-/- and controls had similar left ventricular hypertrophy and cardiac insufficiency, endothelial function was better in LysMETB-/- at both baseline and after Ang II (% dilation of basilar artery in response to CO2, LysMETB-/- vs. controls: baseline: 20 vs.11%, p<0.01; at 6 weeks: 11 vs.0%, p<0.01). Baseline renal function and proteinuria did not differ between groups. After Ang II, LysMETB-/-showed similar renal function compared to controls but less proteinuria (urine albumin:creat, mg/mmol: 208 ± 10 vs. 530 ± 25, p<0.01), glomerulosclerosis (34 ± 2 vs. 61 ± 4%, p<0.001), and fewer renal MΦ compared to controls (F4/80 staining per high power field, LysMETB-/- vs. controls: 1.1 ± 0.7 vs.3.2 ± 0.5%, p=0.02), although similar levels of CD3+ T cells. Plasma ET-1 was no different at baseline but increased more in LysMETB-/- with Ang II (LysMETB-/- vs. controls after 6 weeks Ang II: 3.7 ± 0.7 vs.1.4 ± 0.2 pg/ml, p=0.03). Urine ET-1 was similar baseline and 6 weeks.
Deletion of the MΦ ETBR is associated with a blunting of the effects of systemic Ang II infusion as reflected by less endothelial dysfunction, reduced inflammation and end-organ damage. The mechanisms for these effects are the focus of ongoing research.

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