2020
DOI: 10.1093/eurheartj/ehz915
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Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction

Abstract: Aims Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). Methods and … Show more

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Cited by 94 publications
(63 citation statements)
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“…In considering the role(s) of PHACTR1 in endothelial cells, the consequences of lower PHACTR1 or higher endothelin-1 in these cells could be additive or synergistic with effects in macrophages, as these two cell types play complementary and interactive roles in atherosclerosis(2). Moreover, the endothelial hypothesis may also have relevance to non-atherosclerotic vascular diseases associated with rs9349379-G, including migraine headache, arterial dissection, fibromuscular dysplasia, hypertension, and coronary microvascular dysfunction(28,60,61). Except for coronary microvascular dysfunction, the risk of these non-atherosclerotic vascular diseases is lower in carriers of the rs9349379-G variant in contrast to the higher risk of CAD conferred by rs9349379-G, indicating that future work is needed to link the polymorphism to these diseases.In summary, we present new roles for PHACTR1, MLC, and PP1 in efferocytosisand show that the PHACTR1 intronic rs9349379 CAD risk allele lowers the fully functional form of PHACTR1 protein and impairs efferocytosis in human atherosclerotic lesional macrophages and HMDMs.…”
mentioning
confidence: 99%
“…In considering the role(s) of PHACTR1 in endothelial cells, the consequences of lower PHACTR1 or higher endothelin-1 in these cells could be additive or synergistic with effects in macrophages, as these two cell types play complementary and interactive roles in atherosclerosis(2). Moreover, the endothelial hypothesis may also have relevance to non-atherosclerotic vascular diseases associated with rs9349379-G, including migraine headache, arterial dissection, fibromuscular dysplasia, hypertension, and coronary microvascular dysfunction(28,60,61). Except for coronary microvascular dysfunction, the risk of these non-atherosclerotic vascular diseases is lower in carriers of the rs9349379-G variant in contrast to the higher risk of CAD conferred by rs9349379-G, indicating that future work is needed to link the polymorphism to these diseases.In summary, we present new roles for PHACTR1, MLC, and PP1 in efferocytosisand show that the PHACTR1 intronic rs9349379 CAD risk allele lowers the fully functional form of PHACTR1 protein and impairs efferocytosis in human atherosclerotic lesional macrophages and HMDMs.…”
mentioning
confidence: 99%
“…Zibotentan tested at clinically relevant concentrations completely prevented the effect of endothelin-1. This study indicates that ETA receptor antagonism in this group of patients may have therapeutic benefits [ 168 , 169 ].…”
Section: Coronary Microvascular Dysfunctionmentioning
confidence: 92%
“…Genetic factors , female sex, smoking, inflammation, and illicit drug (cocaine, etc.) associations are also relevant [13][14][15][16][17].…”
Section: Vasomotor Disordersmentioning
confidence: 99%
“…For example, the Precision Medicine With Zibotentan in Microvascular Angina is a randomized, placebo-controlled, clinical trial of treatment for 12 weeks with the endothelin A receptor-selective antagonist, zibotentan [67]. The eligibility criteria require evidence of myocardial ischemia and/or microvascular dysfunction according to the COVADIS criteria and in addition, the population is enhanced with the G-risk allele rs9349379, which is a distal regulator of the endothelin gene [13]. The primary outcome is exercise duration on the Bruce treadmill exercise test protocol.…”
Section: Stratified Medicinementioning
confidence: 99%