Human Urotensin II Promotes Hypertension and Atherosclerotic Cardiovascular Diseases

Abstract

Human urotensin II (U-II), the most potent vasoconstrictor undecapeptide identified to date, and its receptor (UT) are involved in the pathogenesis of systemic and pulmonary hypertension. Here, we review recent advances in our understanding of the pathophysiology of U-II with particular reference to its role in atherosclerotic cardiovascular diseases. Single-nucleotide polymorphisms of U-II gene (S89N) are associated with onset of essential hypertension, type II diabetes mellitus, and insulin resistance in the Asian population. Plasma U-II levels are elevated in patients with vascular endothelial dysfunction-related diseases such as essential hypertension, diabetes mellitus, atherosclerosis, ischemic heart disease, and heart failure. Chronic infusion of U-II enhances atherosclerotic lesions in the aorta in apolipoprotein E-knockout mice. In human atherosclerotic plaques from the aorta and coronary and carotid arteries, U-II is expressed at high levels in endothelial cells (ECs) and lymphocytes, whereas UT is expressed at high levels in vascular smooth muscle cells (VSMCs), ECs, monocytes, and macrophages. U-II stimulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in human ECs as chemoattractant for monocytes, and accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages. U-II produces reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate oxidase activation in human VSMCs, and stimulates VSMC proliferation with synergistic effects when combined with ROS, oxidized LDL, and serotonin. Clinical studies demonstrated increased plasma U-II levels in accordance with the severity of carotid atherosclerosis in patients with essential hypertension and that of coronary artery lesions in patients with ischemic heart disease. Here, we summarize the key roles of U-II in progression of hypertension and atherosclerotic cardiovascular diseases.

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

“…Transforming growth factor-a can trigger transition from epithelial to mesenchymal phenotype through epidermal growth factor receptor, and might, like high mobility group AT-hook 1 previously described, be implicated in neointimal formation in PAH (33). UTS2 was previously associated with PH and vascular diseases (34), and UTS2 expression by PAEC and smooth muscle cells was significantly enhanced in rats with PH induced by aortocaval shunting (35). However, the functional impact of increased UTS2 gene expression in PAH PAEC is unknown.…”

Increased Plasma Urotensin-II and Carotid Atherosclerosis are Associated with Vascular Dementia

“…None of the subjects were taking drugs that influence cognitive performance and had inflammatory diseases. Patients with heart or renal failure and liver cirrhosis known to increase plasma U levels were excluded by history and routine laboratory examination 14) . All participants abstained from smoking for only the night before blood sampling, because smoking within 10 minutes increases plasma U levels 17) .…”

“…Levels of U and UT expression are up-regulated by inflammatory cytokines, such as interferon-, IL-6, and IL-1 , and by hypoxia (ischemia) and mechanical stimuli [34][35][36][37] . U contributes to the development of atherosclerosis by inducing macrophage foam cell formation, EC and VSMC proliferation, and extracellular matrix production 14,38,39) . U accelerates macrophage foam cell formation by up-regulating acyl-CoA:cholesterol acyltransferase-1 38) , and has synergistic interactions with mildly oxidized LDL in inducing VSMC proliferation at the highest rate among vasoactive agents 40) .…”

“…This peptide is known as the most potent vasoconstrictor identified to date 13) . U in circulating blood is produced mainly by the cardiovascular system, liver, and kidneys 14) . Plasma levels of U are increased in vascular endothelial dysfunction-related diseases, such as hypertension, ischemic heart disease, congestive heart failure, diabetes mellitus, and renal failure, and are positively correlated with systolic blood pressure (BP) and severity of atherosclerosis [14][15][16] .…”

“…U in circulating blood is produced mainly by the cardiovascular system, liver, and kidneys 14) . Plasma levels of U are increased in vascular endothelial dysfunction-related diseases, such as hypertension, ischemic heart disease, congestive heart failure, diabetes mellitus, and renal failure, and are positively correlated with systolic blood pressure (BP) and severity of atherosclerosis [14][15][16] . U (molecular weight: 1388) is regarded as a biomarker for atherosclerosis and vascular disease 14) ; however, the association between U and VaD is not clear.…”