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

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.

Endothelial overexpression of endothelin-1 modulates aortic, carotid, iliac and renal arterial responses in obese mice

“…Since nitric oxide synthase inhibition attenuated the relaxations in preparations from WT rather than TET het mice, facilitated hyperpolarization by ET-1 [61] cannot be excluded for these renal arterial preparations. Preserved nitric oxide-mediated relaxations in the aortae of obese TET het mice are in line with the findings in endothelial ET-1 overexpressing ApoE-deficient mice fed a high-fat diet [63] .…”

The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

“…Recently, a study indicated that ethanolic extract of propolis inhibits atherosclerotic lesion formation in ApoE −/− mice fed a high-fat diet, probably by regulating the inflammatory reaction and inhibiting ET-1 (Fang et al 2013 ). Overexpression of ET-1, particularly in the endothelium of mice with atherosclerosis, is accompanied by a decrease in endothelial signalling pathways responsible for endothelium-dependent relaxation and an increase in the activity of sensitive voltage-dependent potassium channels (Mian et al 2013 ). ROS are important physiological messengers in vascular cells and their overproduction contributes to the progression of atherosclerosis (Freund-Michel et al 2013 ).…”

The role of potassium channels in the endothelial dysfunction induced by periodontitis

“…EDH has been proposed to promote vasodilator response action through the initial activation of K Ca 2.3 and K Ca 3.1, which are present in the endothelium 10 and are sensitive to inhibition by a combination of apamin and TRAM-34. 25 , 26 Interestingly, the compensated response to acetylcholine 21 days after ligature placement was inhibited by the blockade of endothelial potassium channels with the combination of apamin plus TRAM-34. This suggests that endothelial calcium-activated potassium channels have a predominant involvement in restoring acetylcholine response.…”

“…This could explain why some studies have reported normal endothelium-dependent relaxation in models of atherosclerosis. 25 …”