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.

Aims/hypothesis The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes. Methods Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg −1 day −1 ) or hydralazine (80 mg kg −1 day −1 ) for 6 weeks, and the protective effects were extensively compared among groups.Results All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22 phox -related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2′-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren. Conclusions/interpretation Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

Abstract-The molecular mechanism underlying aldosterone/salt-induced cardiovascular injury remains to be defined.This work was undertaken to determine the role of apoptosis signal-regulating kinase 1 (ASK1) in the mechanism underlying aldosterone-induced cardiac injury in vivo. We compared the in vivo effects of 4 weeks of aldosterone/salt treatment on wild-type and ASK1-deficient mice. Aldosterone infusion plus high salt intake in wild-type mice significantly increased blood pressure and urinary albumin excretion and decreased plasma potassium concentrations, and these effects of aldosterone/salt were not affected by ASK1 deficiency. Thus, ASK1 seems to play a minor role in aldosterone-induced hypertension and renal injury. ASK1 deficiency also failed to affect aldosterone-induced cardiac hypertrophy. However, ASK1 deficiency markedly ameliorated aldosterone-induced cardiac injury, eg, the enhancement of cardiac macrophage infiltration, monocyte chemotactic protein 1 expression, interstitial fibrosis, perivascular fibrosis, and transforming growth factor-␤1 and collagen type I expressions. Thus, ASK1 participates in aldosterone-induced cardiac inflammation and fibrosis. Furthermore, the enhancement of NADPH oxidase-mediated cardiac oxidative stress caused by aldosterone infusion was markedly lessened by ASK1 deficiency, which was associated with the significant amelioration by ASK1 deficiency of aldosterone-induced cardiac Nox2 upregulation. Furthermore, aldosterone/salt treatment significantly enhanced cardiac expression of the angiotensin-converting enzyme and angiotensin II type 1 receptor in wild-type mice, whereas the enhancement of these proteins by aldosterone/salt was abolished by ASK1 deficiency. Our results demonstrate that ASK1 is implicated in aldosterone/salt-induced cardiac inflammation and fibrosis through the enhancement of NADPH oxidase-mediated oxidative stress and the upregulation of the cardiac renin-angiotensin system. (Hypertension. 2009;54:544-551.)

Abstract-The protective effect of aliskiren, a direct renin inhibitor, against hypertensive cardiovascular and renal injury remains to be defined. This study was undertaken to examine the protective effects of the combination of aliskiren and valsartan, an angiotensin receptor blocker, against cardiovascular and renal injury. Endothelial NO synthase-deficient mice, subjected to cuff injury of femoral artery, were divided into 5 groups and were treated with the following: (1) vehicle; (2) aliskiren (25 mg/kg per day); (3) valsartan (8 mg/kg per day); (4) combined aliskiren (12.5 mg/kg per day) and valsartan (4 mg/kg per day); and (5) hydralazine (10 mg/kg per day) for 4 weeks. Aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; prevented cuff injury-induced arterial intimal thickening; and reduced urinary albumin excretion, glomerular inflammation, and glomerulosclerosis in endothelial NO synthasedeficient mice. These beneficial effects of aliskiren and valsartan were associated with the significant attenuation of oxidative stress in these tissues. Hence, aliskiren and valsartan markedly exert the protective effects against cardiovascular and renal injury through the reduction of oxidative stress. Furthermore, compared with monotherapy with aliskiren or valsartan, the combination of a half dose of these drugs more greatly improved the above-mentioned cardiovascular and renal injuries of endothelial NO synthase-deficient mice, which were associated with greater attenuation of tissue oxidative stress by the combination therapy. Thus, the combination of aliskiren and valsartan exerts the synergistic organ-protective effects through synergistic attenuation of oxidative stress. The combination of aliskiren and valsartan seems to be a promising therapeutic strategy for hypertensive organ injury caused by endothelial NO synthase dysfunction. Key Words: eNOS Ⅲ oxidative stress Ⅲ combination therapy Ⅲ synergistic effect Ⅲ inflammation A ccumulating experimental and clinical evidence support the idea the renin-angiotensin system (RAS) plays a key role in the pathophysiology and development of hypertension, cardiac diseases, atherosclerosis, and renal diseases in a broad range of patients. 1 Mechanistically, conventional RAS blockers, angiotensin-converting enzyme inhibitor and angiotensin II type 1 (AT1) receptor blocker (ARB), attenuate feedback inhibition of renal renin release by suppressing the production and the action, respectively, of angiotensin II, which results in the increase in plasma renin activity. 1 Moreover, plasma renin activity is regarded as a risk factor for myocardial infarction in hypertensive patients. 2,3 Therefore, it is still unclear whether treatment with angiotensin-converting enzyme inhibitor or ARB allows optimized RAS suppression in patients with hypertension or cardiovascular and renal diseases.Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hyp...

Our work demonstrated that candesartan significantly potentiated the protective effects of pioglitazone against cardiorenal and vascular injury, and diabetes in obese type 2 diabetic mice. Thus, the combination of pioglitazone with candesartan is potentially a promising therapeutic strategy for type 2 diabetes.