Effect of metoprolol on vulnerable plaque in rabbits by changing shear stress around plaque and reducing inflammation.
ABSTRACT The beta-adrenoceptor antagonists are known to reduce cardiovascular events, but less is known about their effects on vulnerable plaque. The purpose of this study is to explore the role of metoprolol on vulnerable plaque and the possible mechanism. Vulnerable plaque model was established by local transfection with p53 gene in New Zealand Rabbits. Metoprolol treatment attenuated vessel positive remodeling and reduced vulnerability index (1.61+/-0.58 vs. 2.33+/-0.12, P<0.01). Although the difference did not reach statistical significance, the rate of rupture of atherosclerotic plaque (31% vs. 75%) and intima-media thickness (0.05+/-0.01 vs. 0.08+/-0.01 cm) were less in the metoprolol group than in the control group. The level of shear stress-related inflammatory cytokines such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), matrix metalloproteinase 1 (MMP-1), were lower in the metoprolol group than in the control group (P<0.01). Compared with control group, total cholesterol and low-density lipoprotein cholesterol were lower (P<0.01) in the metoprolol group. After metoprolol treatment, shear stress increased, and was not different to baseline (physiological shear stress, P>0.05). Shear stress and vulnerability index showed a negative correlation. These findings suggest that metoprolol could inhibit the development of atherosclerosis and stabilize vulnerable plaque by regulation of lipid and reduction of inflammation, in which the change from low shear stress to physiological shear stress around plaque may play an important role.
- SourceAvailable from: Sandra M Bovens[Show abstract] [Hide abstract]
ABSTRACT: Atherosclerosis is intimately coupled to blood flow by the presence of predilection sites. The coupling is through mechanotransduction of endothelial cells and approximately 2000 gene are associated with this process. This paper describes a new platform to study and identify new signalling pathways in endothelial cells covering an atherosclerotic plaque. The identified networks are synthesized in primary cells to study their reaction to flow. This synthetic approach might lead to new insights and drug targets.FEBS letters 05/2012; 586(15):2164-70. · 3.54 Impact Factor
- Industrial Crops and Products. 11/2011; 34(3):1410-1417.
- [Show abstract] [Hide abstract]
ABSTRACT: The MMPs and their inhibitors [tissue inhibitor of MMPs (TIMPs) ] form the mainstay of extracellular matrix homeostasis. They are expressed in response to numerous stimuli including cytokines and GPCR activation. This review highlights the importance of adrenoceptors and phosphoprotein phosphatases (PPP) in regulating MMPs in the cardiovascular system, which may help explain some of the beneficial effects of targeting the adrenoceptor system in tissue remodelling and will establish emerging crosstalk between these three systems. Although - and β-adrenoceptor activation increases MMP but decreases TIMP expression, MMPs are implicated in the growth stimulatory effects of adrenoceptor activation through transactivation of epidermal growth factor receptor. Furthermore, they have recently been found to catalyse the proteolysis of β-adrenoceptors and modulate vascular tone. While the mechanisms underpinning these effects are not well defined, reversible protein phosphorylation by kinases and phosphatases may be key. In particular, PPP (Ser/Thr phosphatases) are not only critical in resensitization and internalization of adrenoceptors but also modulate MMP expression. The interrelationship is complex as isoprenaline (ISO) inhibits okadaic acid [phosphoprotein phosphatase type 1/phosphoprotein phosphatase type 2A (PP2A) inhibitor]-mediated MMP expression. While this may be simply due to its ability to transiently increase PP2A activity, there is evidence for MMP-9 that ISO prevents okadaic acid-mediated expression of MMP-9 through a β-arrestin, NF-κB-dependent pathway, which is abolished by knock-down of PP2A. It is essential that crosstalk between MMPs, adrenoceptors and PPP are investigated further as it will provide important insight into how adrenoceptors modulate cardiovascular remodelling, and may identify new targets for pharmacological manipulation of the MMP system.British Journal of Pharmacology 05/2012; 166(4):1225 - 1243. · 5.07 Impact Factor