TY - JOUR
T1 - Preservation of endothelium-dependent relaxation in atherosclerotic mice with endothelium-restricted endothelin-1 overexpression
AU - Mian, Muhammad Oneeb Rehman
AU - Idris-Khodja, Noureddine
AU - Li, Melissa W.
AU - Leibowitz, Avshalom
AU - Paradis, Pierre
AU - Rautureau, Yohann
AU - Schiffrin, Ernesto L.
PY - 2013/10
Y1 - 2013/10
N2 - In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ETA receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe-/-) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe-/-) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe-/- mice. EDR in mesenteric resistance arteries from 8- and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe -/- compared with Apoe-/- mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe-/-. EDR in eET-1/Apoe -/- mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe-/- compared with wild-type (WT) mice. In eET-1/Apoe-/- mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassiumchannels (Kv) during EDR was increased in eET-1/Apoe-/- compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of Kv are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.
AB - In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ETA receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe-/-) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe-/-) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe-/- mice. EDR in mesenteric resistance arteries from 8- and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe -/- compared with Apoe-/- mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe-/-. EDR in eET-1/Apoe -/- mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe-/- compared with wild-type (WT) mice. In eET-1/Apoe-/- mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassiumchannels (Kv) during EDR was increased in eET-1/Apoe-/- compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of Kv are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.
UR - http://www.scopus.com/inward/record.url?scp=84884624691&partnerID=8YFLogxK
U2 - 10.1124/jpet.113.206532
DO - 10.1124/jpet.113.206532
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C2 - 23902937
AN - SCOPUS:84884624691
SN - 0022-3565
VL - 347
SP - 30
EP - 37
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -