Original ArticleThe up-regulation of endothelin-1 and down-regulation of miRNA-125a-5p, -155, and -199a/b-3p in human atherosclerotic coronary artery
Introduction
Atherosclerotic plaque (AP) rupture is considered the most important mechanism that underlies the onset of acute ischemic syndromes, including stroke, unstable angina, acute myocardial infarction, and sudden death [1], [2]. Imaging modalities which involve noninvasive and invasive methods are developed and validated to accurately characterize APs, but they may destabilize plaques and cause subsequent clinical events. Furthermore, circulating biomarkers are being investigated as a measure of plaque vulnerability [2]. Although many molecular approaches have been performed, the pathophysiology of plaque progress and rupture is not completely understood.
Previous studies indicated that endothelin-1 (ET-1) played a vital role in the pathophysiology of plaque progress and rupture. ET-1 is synthesized and released mostly from endothelial cells [3]. Besides this predominant source, experiments in vivo showed that ET-1 was also synthesized in the macrophages, fibroblasts, cardiomyocytes, and other cells [4]. It was reported that ET-1 had mitogenic effects on smooth muscle cells and fibroblasts and it stimulated synthesis of inflammatory mediators in macrophages and fibronectin in smooth muscle cells [5], [6]. Moreover, ET-1 was proved to activate nuclear factor-ΚB, a key transcription factor of inflammation-cascade, in human monocytes [7]. The constrictor and chemoattractant properties of ET-1 also supported its role in the pathogenesis of atherosclerosis [8].
One of the possible explanations for the up-regulation of ET-1 might be the down-regulation of its upstream microRNAs. MicroRNAs are short non-coding RNAs that regular protein expression at the transcriptional level by inhibiting mRNA translation or inducing its degradation [9]. Meanwhile, they are considered to be novel biomarkers for diagnosing and preventing the coronary artery disease, since they act as important regulators in inflammation and angiogenesis, both of which are core characteristics of plaque vulnerability [10], [11]. In recent studies, several expression profiles of miRNAs in APs were reported. They indicated that the expression of specific miRNA signatures might contribute to the plaque evolution toward an unstable phenotype [11], [12], [13].
In the present study, we determined the expression of ET-1 and angiotensin II (Ang II) in pericardial fluid from coronary atherosclerotic patients. Then, we conducted immunohistochemical staining (IHC) and semiquantified the proteins in the diseased vessel wall. Furthermore, we determined the expression of miRNAs targeting ET-1 in the atherosclerotic coronary arteries.
Section snippets
Autopsy cases
The study included medicolegal autopsy cases (n=25) in Sun Yat-Sen University Zhongshan School of Medicine. All the autopsies were conducted within 72 h after death. The cases were subdivided into two groups: AP group (n=12) and non-AP group (n=13) (details shown in Table 1). The ethnicity of all the selected cases was the Chinese Han. The individuals in AP group suffered atypical chest pains and sudden deaths resulting from acute myocardial infarction, while the patients in non-AP group
The expression of ET-1 and Ang II in the pericardial fluid
A four-parameter logistic curve-fit was generated using computer software to transfer optical density (OD) values to protein concentrations. Compared with those in non-AP group (mean±S.D., 0.32±0.29) (pg/ml), pericardial fluid samples in AP group showed a significantly high ET-1 level (mean±S.D., 0.82±0.51, P<.01) (pg/ml) (Fig. 1a). In contrast, there was no significantly statistical difference in the levels of Ang II between AP group (mean±S.D., 44.33±17.08) (pg/ml) and non-AP group
Discussion
Largely owing to the vast literature on the role of Ang II in the inflammation response of vessel walls, it has become common to believe that Ang II, the final effector of the renin-angiotensin system (RAS), should be involved in the initiation and development of atherosclerosis [15]. However, our data obtained in human pericardial fluid and human coronary artery tissues showed that Ang II had no significant difference in pericardial fluid between the two groups. Even, it showed a significantly
Acknowledgments
The authors are deeply grateful to coworkers in the Sun Yat-Sen University Zhongshan School of Medicine. This study was supported by the Provincial Natural Science Fund Project of Guangdong (Grant No.: S2013010016749), National Natural Science Foundation of China (Grant No.: 81300106).
References (36)
- et al.
From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization
Trends Cardiovasc Med
(2007) - et al.
The effect of endothelin-1 on nuclear factor kappa B in macrophages
Biochem Biophys Res Commun
(2001) - et al.
Endothelin-1 and atherosclerosis: potential complications associated with endothelin-receptor blockade
Atherosclerosis
(2002) - et al.
miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study
Atherosclerosis
(2011) - et al.
Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries
Biochem Biophys Res Commun
(1993) - et al.
Endothelin-1 is increased overlying atherosclerotic plaques in human arteries
Atherosclerosis
(1996) - et al.
miR-125b regulates calcification of vascular smooth muscle cells
Am J Pathol
(2011) - et al.
MicroRNA-155 regulates lipid uptake, adhesion/chemokine marker secretion and SCG2 expression in oxLDL-stimulated dendritic cells/macrophages
Int J Cardiol
(2011) - et al.
Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans
Clin Chim Acta
(2011) - et al.
Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage
Arterioscler Thromb Vasc Biol
(2005)
Secretory pathways in endothelin synthesis
Br J Pharmacol
Endothelin system: the double-edged sword in health and disease
Annu Rev Pharmacol Toxicol
Suppression of endothelin-1-induced mitogenic responses of human aortic smooth muscle cells by interleukin-1 beta
J Clin Invest
Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone
J Physiol Pharmacol
MicroRNAs: novel regulators of the heart
J Thorac Dis
Circulating microRNAs: novel biomarkers for cardiovascular diseases?
Eur Heart J
microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans
Thromb Haemost
A unique microRNA signature associated with plaque instability in humans
Stroke
Cited by (48)
Circulating miRNAs as Biomarkers for Diagnosis, Surveillance, and Postoperative Follow-Up of Abdominal Aortic Aneurysms
2023, Annals of Vascular SurgeryPhysical exercise and the functions of microRNAs
2022, Life SciencesCitation Excerpt :On the other hand, ultramarathon runners showed 28 times greater expression of miRNA-125a-5p compared to control subjects, while miRNA-let-7e and -126 did not differ statistically between ultramarathon runners and controls [150]. miRNA-125a can be downregulated in patients with atherosclerosis, and both miRNA-125a-5p and -126 have been shown to diminish ox-LDL uptake in endothelial cells and monocytes, and thus may protect against the development of atherosclerosis [151]. In terms of cardioprotection and insulin response, physical exercise can reduce miRNA-135b, -144, -206, -34a, -122, -135b, -144, -486, and -206, stimulating genes that are important for glucose metabolism, such as IRS1, FOXO1, and GSK3β, which are related to the regulation of the acute insulin response to glucose and insulin secretion, as well as glycogen formation [152,153].
Molecular mechanisms involved in pre-eclampsia through expressional regulation of endothelin-1
2022, PlacentaCitation Excerpt :Enquobahrie et al. reported down-regulation of miR-1 levels in placental samples of pre-eclamptic pregnants, similar to our findings [22]. Another study showed that ET-1 levels were found significantly higher in coronary arteries from atherosclerotic plaque group with decreased levels of miR-125b [21]. Li et al. showed that inhibition of ET-1 expression in vascular endothelial cells by miR-125a/b-5p [9].
The role of endothelial miRNAs in myocardial biology and disease
2020, Journal of Molecular and Cellular CardiologyCitation Excerpt :In vitro approaches, including luciferase reporter assays, overexpression cell models, and western blotting, indicate a direct interaction between miR-125a/b and the 3′ untranslated region of prepro-endothelin-1 mRNA. In accordance with this, upregulation of endothelin-1 was detected in aortic tissue upon administration of miR-125a/b inhibitors to stroke-prone spontaneously hypertensive rats and in pericardial fluid of patients with acute coronary syndrome [115,116]. Another important paracrine factor for vascular pathology, which is partly regulated in a miRNA-dependent manner, is neuregulin-1.
Conflicts of interest. The authors declare that there are no conflicts of interest.
Name of grants: Provincial Natural Science Fund Project of Guangdong (Grant No.: S2013010016749); National Natural Science Foundation of China (Grant No.: 81300106).