The purpose of this work was to test whether brain-penetrating angiotensin-converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain-penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)₁₋₄₀. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing Aβ in the brain. Perindopril, without affecting brain Aβ deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.

Abstract-Dietary obesity is associated with type 2 diabetes and cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in obesity/diabetes-associated cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with olmesartan, an angiotensin II type 1 receptor blocker, to elucidate the role of angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with olmesartan markedly suppressed cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by obesity/diabetes. Moreover, olmesartan suppressed the disruption of the vascular endothelial NO synthase dimer in diabetic mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. These beneficial effects of olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation. Key Words: diabetes Ⅲ obesity Ⅲ angiotensin Ⅲ ASK1 Ⅲ reactive oxygen species Ⅲ vascular endothelial function Ⅲ cardiac injury O besity, particularly dietary obesity, is associated with type 2 diabetes 1 and an increased risk of cardiovascular diseases. 2-5 However, the underlying mechanism is poorly understood. Accumulating experimental and clinical evidence indicate that the renin-angiotensin system is involved not only in hypertension but also in various cardiovascular diseases. 6 Furthermore, emerging experimental and clinical data support the notion that the renin-angiotensin system participates in the pathophysiology of obesity and type 2 diabetes, 7-13 although the underlying mechanism remains to be elucidated.Reactive oxygen species (ROS) are supposed to be involved in obesity, 14 -17 insulin resistance, diabetes, 1,18 and cardiovascular diseases. 19,20 Apoptosis signal regulating kinase-1 (ASK1), one of the mitogen-activated protein kinase kinase kinases, is markedly activated by ROS and plays a critical role in a variety of cellular responses induced by ROS, including cell apoptosis, growth, differentiation, gene expression, etc. 21-23 Previous...

Abstract-The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67 phox -related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia. (Hypertension. 2011;58:635-642.) • Online Data Supplement Key Words: vascular dementia Ⅲ chronic cerebral ischemia Ⅲ oxidative stress Ⅲ renin Ⅲ working memory Ⅲ white matter lesion S ubcortical vascular dementia, 1,2 one of the major subtypes of vascular dementia, is characterized by white matter (WM) changes and lacunar infarctions and is caused by a chronic decrease in cerebral blood flow attributed to small vessel disease. However, the precise mechanism of subcortical vascular dementia remains to be defined. A preventive or therapeutic strategy for subcortical vascular dementia has not been fully established.Aliskiren is the first in a new class of direct renin inhibitors approved for the treatment of hypertension. Differing from angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, aliskiren 3,4 blocks the renin-angiotensin system (RAS) by directly inhibiting the enzymatic activity of renin and thereby suppressing the formation of angiotensin I from angiotensinogen. Aliskiren has been suggested to be at least as effective as the conventional RAS blockers in blood pressure (BP)-l...