Urotensin II Promotes Atherosclerosis in Cholesterol-Fed Rabbits

Abstract

Urotensin II (UII) is a vasoactive peptide composed of 11 amino acids that has been implicated to contribute to the development of cardiovascular disease. The purpose of this study was to investigate whether UII affects the development of atherosclerosis in cholesterol-fed rabbits. UII was infused for 16 weeks through an osmotic mini-pump into male Japanese White rabbits fed on a high-cholesterol diet. Plasma lipids and body weight were measured every 4 weeks. Aortic atherosclerotic lesions along with cellular components, collagen fibers, matrix metalloproteinase-1 and -9 were examined. Moreover, vulnerability index of atherosclerotic plaques was evaluated. UII infusion significantly increased atherosclerotic lesions within the entire aorta by 21% over the control (P = 0.013). Atherosclerotic lesions were increased by 24% in the aortic arch (P = 0.005), 11% in the thoracic aorta (P = 0.054) and 18% in the abdominal aorta (P = 0.035). These increases occurred without changes in plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or body weight. Immunohistochemical staining revealed that macrophages and matrix metalloproteinase-9 were significantly enhanced by 2.2-fold and 1.6-fold in UII group. In vitro studies demonstrated that UII up-regulated the expression of vascular cell adhesion protein-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells, which was inhibited by the UII receptor antagonist urantide. In conclusion, our results showed that UII promotes the development of atherosclerotic lesions and destabilizes atherosclerotic plaques in cholesterol-fed rabbits.

Autocrine Human Urotensin II Enhances Macrophage-Derived Foam Cell Formation in Transgenic Rabbits

“…As a vasoactive cyclic peptide, circulating UII is involved in the progression of atherosclerosis and identified to be a proatherogenic factor, based on the current information from several laboratories and our previous study [ 5 – 10 ]. The role of autocrine UII in the development of atherosclerosis remains unclear.…”

“…To identify the hUII expression levels in transgenic rabbits, protein samples extracted from alveolar macrophages of the transgenic rabbits and their nontransgenic littermates were prepared, as described previously, and analyzed by electrophoresis on 10% SDS-polyacrylamide gels, followed by Western blotting and probing with a polyclonal antibody against hUII (Atlas Antibodies, Sweden) [ 10 ].…”

“…At the end of the experiment, the rabbits were sacrificed by an overdose of sodium pentobarbitone for the analysis of the atherosclerotic arterial lesions. The aortas were en face stained with Sudan IV (Yongsheng Chemical Co., China) for evaluation of the gross atherosclerotic lesions, as described previously [ 10 , 14 ]. Briefly, the whole aortas were photographed using a digital camera and the sudanophilic area was measured using an image analysis system.…”

“…UII was expressed predominantly in the cardiovascular and central nervous systems as well as in endocrine tissue and, particularly, in human atherosclerotic lesions [ 4 , 5 ]. Epidemiological, clinical, and experimental studies have shown that an increasing level of circulating UII is involved in the development of atherosclerosis [ 5 – 10 ]. Circulating UII increases plasma reactive oxygen species (ROS) and oxidized low-density lipoprotein (ox-LDL) and upregulates the expression of vascular cell adhesion protein-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), scavenger receptors (CD36 and scavenger receptor class A), and acyl-CoA, which are important molecules in the initiation and progression stages of atherosclerosis lesion formation [ 8 – 10 ].…”

The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy

“…Several mechanisms underlying the U‐II and UT receptor‐mediated cardiac hypertrophy have been suggested, including up‐regulation of inflammatory cytokines and reactive oxygen species (Johns et al ., ; Liu et al ., ), and activation of signalling pathways such as Gα q ‐ and Ras‐dependent, MAPKs, and the Akt/GSK‐3β signalling pathways (Tzanidis et al ., ; Onan et al ., ; Gruson et al ., ). Most recently, a deleterious elevation of the UT system has been found in the metabolic syndrome, which is a critical risk factor for cardiovascular diseases (Barrette and Schwertani, ; You et al ., ; Li et al ., ). These results raise the possibility that U‐II and UT receptors are involved in the pathogenesis of cardiac remodelling.…”