Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse.

RATIONALE: Angiotensin-converting enzyme (ACE)2 opposes the actions of angiotensin (Ang) II by degrading it to Ang 1-7. 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-α. 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 Ace2 deficiency is associated with upregulation of putative mediators of atherogenesis and enhances responsiveness to proinflammatory stimuli. In atherosclerosis-prone ApoE KO mice, these changes potentially contribute to increased plaque accumulation. These findings emphasize the potential utility of ACE2 repletion as a strategy to reduce atherosclerosis.

Providing learning support to nursing students: a study of two universities.

In universities where significant numbers of nursing students come from non-traditional backgrounds, and where an equally significant proportion of students have English as a second language, provision of learning support is essential to ensure success and progression, and to prevent attrition. This paper presents an evaluative study of the support services provided to undergraduate nursing students in two universities in the United Kingdom (UK). Both universities have significant numbers of students from non-traditional backgrounds and who have English as a second language, and both institutions have in place a large array of student support mechanisms. The aims of the study were to identify all existing student support mechanisms across the two universities, to illuminate the profile of students who enter pre-registration programmes at the two universities (age, gender, educational background) and to measure the perceptions of students of the use and usefulness of the support mechanisms provided by their university. Survey method evaluative research was the chosen research approach. Findings showed that the support services that appear to have the greatest impact on student success in their nursing programme are the programme leaders/module teachers, small study skills groups (known as APPL and L2L) and, for the 50% of students who required it, academic literacy and numeracy support sessions. For students who have English as a second language and with non-traditional entry qualifications, numeracy and academic literacy support is particularly valued.

ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes.

OBJECTIVE: The degradation of angiotensin (Ang) II by ACE2, leading to the formation of Ang 1-7, is an important step in the renin-angiotensin system (RAS) and one that is significantly altered in the diabetic kidney. This study examines the role of ACE2 in early renal changes associated with diabetes and the influence of ACE2 deficiency on ACE inhibitor-mediated renoprotection. RESEARCH DESIGN AND METHODS: Diabetes was induced by streptozotocin in male c57bl6 mice and ACE2 knockout (KO) mice. After 5 weeks of study, animals were randomized to receive the ACE inhibitor perindopril (2 mg x kg(-1) x day(-1)). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg x kg(-1) x day(-1)) and followed for an additional 5 weeks. Markers of renal function and injury were then assessed. RESULTS: Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1-7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhanced, associated with an increase in blood pressure. However, renal hypertrophy and fibrogenesis were reduced in diabetic mice with ACE2 deficiency, and hyperfiltration was attenuated. Diabetic wild-type mice treated with an ACE inhibitor experienced a reduction in albuminuria and blood pressure. These responses were attenuated in both diabetic ACE2 KO mice and diabetic mice receiving MLN-4760. However, other renoprotective and antifibrotic actions of ACE inhibition in diabetes were preserved in ACE2-deficient mice. CONCLUSIONS: The expression of ACE2 is significantly modified by diabetes, which impacts both pathogenesis of kidney disease and responsiveness to RAS blockade. These data indicate that ACE2 is a complex and site-specific modulator of diabetic kidney disease.