Objective: Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis. Methods and Results:C57Bl6, Ace2 knockout (KO), apolipoprotein E (ApoE) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic (ApoE KO) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-␣. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10 ؊7 mol/L). Conclusions: Genetic

Objective-Traditional risk factors for coronary artery disease (CAD) fail to adequately distinguish patients who have atherosclerotic plaques susceptible to instability from those who have more benign forms. Using plasma lipid profiling, this study aimed to provide insight into disease pathogenesis and evaluate the potential of lipid profiles to assess risk of future plaque instability. Methods and Results-Plasma lipid profiles containing 305 lipids were measured on 220 individuals (matched healthy controls, nϭ80; stable angina, nϭ60; unstable coronary syndrome, nϭ80) using electrospray-ionisation tandem mass spectrometry. ReliefF feature selection coupled with an L2-regularized logistic regression based classifier was used to create multivariate classification models which were verified via 3-fold cross-validation (1000 repeats). Models incorporating both lipids and traditional risk factors provided improved classification of unstable CAD from stable CAD (C-statisticϭ0.875, 95% CI 0.874 -0.877) compared with models containing only traditional risk factors (Cstatisticϭ0.796, 95% CI 0.795-0.798). Many of the lipids identified as discriminatory for unstable CAD displayed an association with disease acuity (severity), suggesting that they are antecedents to the onset of acute coronary syndrome. Key Words: acute coronary syndromes Ⅲ atherosclerosis Ⅲ lipids Ⅲ risk factors Ⅲ biomarker A cute coronary syndromes (unstable angina, myocardial infarction, and many cases of sudden cardiac death) are almost invariably the result of atherosclerotic plaque disruption and subsequent thrombosis (atherothrombosis). Although plaque accumulation and development is progressive throughout life, plaques may cycle between being stable and unstable throughout the disease process. Accurate identification of those at risk for unstable coronary syndromes is an important prerequisite to targeted treatment and prevention. However, current screening is limited by the predictive power of available tests, the high cost of these tests, or a combination of both. Furthermore, the ability of these tests to subclassify patients with CAD as having stable or unstable disease has been limited. Conclusion-PlasmaRisk assessment for coronary artery disease (CAD) is currently performed by the evaluation of traditional risk factors (eg, smoking status, body mass index, cholesterol level, blood pressure); by direct measures of arterial structural changes associated with atherosclerosis, such as carotid intima-medial thickness and the coronary artery calcification score; or by testing for myocardial ischemia using stress testing. For the most part, the addition of circulating biomarkers has added little to risk assessment by conventional methods, although the recent reports by Blankenberg et al 1 indicate that risk scores incorporating multiple biomarkers can improve on conventional risk models, and the report of Schnabel et al 2 suggests that this strategy may also be useful in the setting of stable CAD. The development of noninvasive screening tests that c...

The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications.

Authorship note: RJP, CT, and CJR are co-first authors. Conflict of interest: KDGP is chief scientific adviser of Dimerix Limited, a spin-off company of The University of Western Australia that has been assigned the rights to Receptor-HIT. KDGP is an inventor on patents covering the technology (World Intellectual Property [WIPO] patent no. WO/2008/055313, held by Dimerix Limited) and is a shareholder of Dimerix Limited.

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