Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression s

ABSTRACT In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ET A 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 2/2 ) 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 2/2 ) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe 2/2 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 2/2 compared with Apoe 2/2 mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe 2/2 . EDR in eET-1/Apoe 2/2 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 2/2 compared with wild-type (WT) mice. In eET-1/Apoe 2/2 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 potassium channels (K v ) during EDR was increased in eET-1/Apoe 2/2 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 K v are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1

Across the globe in 4 months: two international society of hypertension new investigator symposia in 2014

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