Abstract
Microparticles are membrane vesicles with pro-inflammatory properties. Circulating levels of microparticles have previously been found to be elevated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the effects of in vivo treatment with microparticles, from patients with MetS and from healthy subjects (HS), on ex vivo vascular function in mice. Microparticles isolated from MetS patients or HS, or a vehicle were intravenously injected into mice, following which vascular reactivity in response to vasoconstrictor agonists was assessed by myography with respect to cyclo-oxygenase pathway, oxidative and nitrosative stress. Injection of microparticles from MetS patients into mice induced vascular hypo-reactivity in response to serotonin. Hypo-reactivity was associated with up-regulation of inducible NO-synthase and increased production of NO, and was reversed by the NO-synthase inhibitor (NG-nitro-L-arginine). The selective COX-2 inhibitor (NS398) reduced the contractile effect of serotonin in aortas from mice treated with vehicle or HS microparticles; however, this was not observed within mice treated with MetS microparticles, probably due to the ability of MetS microparticles to enhance prostacyclin. MetS microparticle-mediated vascular dysfunction was associated with increased reactive oxygen species (ROS) and enhanced expression of the NADPH oxidase subunits. Neutralization of the pro-inflammatory pathway Fas/FasL completely prevented vascular hypo-reactivity and the ability of MetS microparticles to enhance both inducible NO-synthase and monocyte chemoattractant protein-1 (MCP-1). Our data provide evidence that microparticles from MetS patients induce ex vivo vascular dysfunction by increasing both ROS and NO release and by altering cyclo-oxygenase metabolites and MCP-1 through the Fas/FasL pathway.
Highlights
Metabolic syndrome (MetS) is associated with glucose intolerance, obesity, ageing, elevated blood pressure and dyslipidaemia, all of which are risk factors associated with cardiovascular morbidity and mortality [1,2]
MetS patients exhibited lower levels of adiponectin compared to control subjects, leptin levels were similar in both groups, supporting insulin resistance within the MetS patients [31]
We demonstrated that i.v. injection of MetS MPs promotes vascular hypo-reactivity in mice
Summary
Metabolic syndrome (MetS) is associated with glucose intolerance, obesity, ageing, elevated blood pressure and dyslipidaemia, all of which are risk factors associated with cardiovascular morbidity and mortality [1,2]. Increased inflammatory factors and reactive oxygen species (ROS) are associated with detrimental cardiovascular alterations linked to MetS. Inflammation is orchestrated by the interactions between inflammatory cells (such as leukocytes) and vascular cells (endothelial and smooth muscle cells) which under activation or apoptosis (for example) lead to the release of circulating microparticles (MPs) [6,7]. The mechanism of MP formation is complex and has yet to be clearly elucidated, due to cell type and stimuli specificity. Evidence suggest that following cell activation or apoptosis, MP formation occurs due to the sustained elevation in cytosolic calcium concentration in addition to the consequent activation of calpain and protein kinases and the inhibition of phosphatases. In addition to MP formation, these changes result in cytoskeletal reorganization and membrane blebbing [6,8,9,10]. The mechanism of MPs clearance from the circulation is currently unknown, but due to their small size, MPs are believed to be more readily diffusible than cells, and are able to escape phagocytosis [11]
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