Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation

Iwai, Masaru; Liu, Hong Wei; Chen, Rui; Ide, Akio; Okamoto, Shoko; Hata, Ryuji; Sakanaka, Masahiro; Shiuchi, Tetsuya; Horiuchi, Masatsugu

doi:10.1161/01.cir.0000138848.58269.80

Cited by 233 publications

(178 citation statements)

References 40 publications

Supporting

Mentioning

165

Contrasting

Unclassified

Order By: Relevance

“…Cerebral blood flow (CBF) was determined by laser speckle flowmetry (Omegazone laser speckle blood flow imager, Omegawave, Inc, Tokyo, Japan, http://www.omegawave.co.jp/ index.html) [36]. A detailed explanation of the conditions is provided in the Materials and Methods Section of Supporting Information.…”

Section: Measurement Of Cbfmentioning

confidence: 99%

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

et al. 2010

View full text Add to dashboard Cite

Increasing evidence shows that administration of bone marrow mononuclear cells (BMMCs) is a potential treatment for various ischemic diseases, such as ischemic stroke. Although angiogenesis has been considered primarily responsible for the effect of BMMCs, their direct contribution to endothelial cells (ECs) by being a functional elements of vascular niches for neural stem/progenitor cells (NSPCs) has not been considered. Herein, we examine whether BMMCs affected the properties of ECs and NSPCs, and whether they promoted neurogenesis and functional recovery after stroke. We compared i.v. transplantations 1 3 10 6 BMMCs and phosphate-buffered saline in mice 2 days after cortical infarction. Systemically administered BMMCs preferentially accumulated at the postischemic cortex and periinfarct area in brains; cell proliferation of ECs (angiogenesis) at these regions was significantly increased in BMMCstreated mice compared with controls. We also found that endogenous NSPCs developed in close proximity to ECs in and around the poststroke cortex and that ECs were essential for proliferation of these ischemia-induced NSPCs. Furthermore, BMMCs enhanced proliferation of NSPCs as well as ECs. Proliferation of NSPCs was suppressed by additional treatment with endostatin (known to inhibit proliferation of ECs) following BMMCs transplantation. Subsequently, neurogenesis and functional recovery were also promoted in BMMCs-treated mice compared with controls. These results suggest that BMMCs can contribute to the proliferation of endogenous ischemia-induced NSPCs through vascular niche regulation, which includes regulation of endothelial proliferation. In addition, these results suggest that BMMCs transplantation has potential as a novel therapeutic option in stroke treatment.

show abstract

Section: Measurement Of Cbfmentioning

confidence: 99%

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

et al. 2010

View full text Add to dashboard Cite

show abstract

“…11 For detection of ethidium, samples were examined with an Axioskop microscope (Axioskop 2 plus with AxioCam, Carl Zeiss) equipped with a computer-based imaging system. The intensity of the fluorescence was analyzed and quantified using computerimaging software (Densitograph, ATTO Corporation).…”

Section: Detection Of Superoxide Anion Production In Brain Sectionsmentioning

confidence: 99%

“…[7][8][9] Moreover, we have reported previously that blockade of RAS with ARBs attenuates ischemic brain damage. 10,11 However, the roles of Ang II in cognitive function are not well defined. In addition, the relationship between continuous activation of the brain RAS and cognitive function is not understood.…”

mentioning

confidence: 99%

Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

et al. 2009

Self Cite

View full text Add to dashboard Cite

Abstract-We examined the possibility that continuous activation of the human brain renin-angiotensin system causes cognitive impairment, using human renin (hRN) and human angiotensinogen (hANG) gene chimeric transgenic (Tg) mice. Cognitive function was evaluated by the shuttle avoidance test once a week from 10 to 20 weeks of age. The avoidance rate in wild-type mice gradually increased. In contrast, the avoidance rate in chimeric hRN/hANG-Tg mice also increased; however, no further increase in avoidance rate was observed from 14 weeks of age, and it decreased thereafter. Cerebral surface blood flow was markedly reduced in 20-week-old hRN/hANG-Tg mice. Superoxide anion production in the brain was already higher in 10-week-old hRN/hANG-Tg mice and further increased thereafter with an increase in NADPH oxidase activity. Moreover, expression of p47 phox and Nox4 in the brain of hRN/hANG-Tg mice also increased. Administration of an angiotensin II type 1 receptor blocker, olmesartan (5.0 mg/kg per day), attenuated the increase in blood pressure and ameliorated cognitive decline with enhancement of cerebral surface blood flow and a reduction of oxidative stress in hRN/hANG-Tg mice. On the other hand, hydralazine (0.5 mg/kg per day) did not improve the decrease in avoidance rate, and did not influence cerebral surface blood flow or oxidative stress in hRN/hANG-Tg mice, in spite of a similar reduction of blood pressure to that by olmesartan. Moreover, we observed that treatment with Tempol improved impaired cognitive function in hRN/hANG-Tg mice. These results suggest that continuous activation of the brain renin-angiotensin system impairs cognitive function via stimulation of the angiotensin II type 1 receptor with a decrease in cerebral surface blood flow and an increase in oxidative stress. Key Words: angiotensin II receptors Ⅲ cognitive function Ⅲ blood flow Ⅲ oxidative stress Ⅲ transgenic mice D ementia is a common serious health problem that impairs quality of life. A continuous decline in cognitive function occurs as the natural aging course in both humans and animal models. Hypertension is a major risk factor for cerebrovascular disease, including stroke, and contributes to the development of vascular dementia. 1 Several clinical studies, such as Perindopril Protection Against Recurrent Stroke Study, Systolic Hypertension in Europe, and Study on Cognition and Prognosis in the Elderly, have shown that antihypertensive drug treatment is associated with reduced cognitive decline. 2-4 However, it is not still clear which classes of antihypertensive drugs provide greater benefits than others.Activation of the renin-angiotensin system (RAS) plays major roles in elevated blood pressure and the development of cerebrovascular disorders. All of the components of the classic RAS have been identified in the brain. 5,6 Recent clinical trials, such as the Losartan Intervention for Endpoint Reduction in Hypertensive Study, Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention, and...

show abstract

“…Our recent study indicates that activation of the human RAS in chimeric transgenic mice with human renin and human angiotensinogen genes exaggerates ischemic brain damage mainly through stimulation of the AT 1 receptor. 13 In contrast, activation of the angiotensin II type 2 (AT 2 ) receptor attenuated brain injury 14 with counter-regulatory effects on the AT 1 receptor. ARBs stimulate AT 2 receptor signaling with unbound Ang II by blocking AT 1 receptor signaling.…”

Section: Protection From Ischemic Brain Damagementioning

confidence: 99%

Effects of angiotensin II receptor blockers on dementia

Mogi

Horiuchi

2009

Hypertens Res

Self Cite

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) is involved in pathological mechanisms of target organ damage as well as the induction of hypertension; therefore, blockade of the RAS has been expected to prevent cardiovascular and cerebrovascular diseases beyond its antihypertensive effects. In spite of the well-characterized role of angiotensin (Ang) II receptor blockers (ARBs) in preventing the onset and recurrence of stroke, the clinical evidence for an effect of ARBs on dementia has not been definitive. However, preliminary experiments raise the possibility that treatment using ARBs may prevent ischemic brain damage and cognitive impairment. Moreover, recent reports have shown that some ARBs prevent amyloid b deposition in the brain and attenuate cognitive impairment in Alzheimer disease models. Furthermore, recent cohort studies indicate that lower incidence of Alzheimer disease is observed in elderly individuals treated with ARBs. These results indicate a beneficial role for ARBs in cognitive impairment associated with vascular disease, Alzheimer disease, metabolic syndrome and other neurodegenerative diseases. Here, we review the effects of ARBs on the brain with a focus on dementia and future therapeutic approaches for elderly people suffering from disabilities. Hypertension Research (2009) 32, 738-740; doi:10.1038/hr.2009 Keywords: dementia; neuroinflammation; neuroprotective; renin-angiotensin system; stroke INTRODUCTION Dementia is a common but serious health problem. An estimated 33 million elderly persons around the world suffer from dementia, and this number is expected to reach 81.1 million by 2040. 1 Dementia impairs quality of life and is associated with a profound disease burden, morbidity and mortality, not only in patients but also in caregivers. 2,3 Therefore, prevention of dementia is a critical need for advanced countries to address. Life style-related disorders, such as hypertension, diabetes mellitus and obesity have been reported to be related to dementia. For example, large prospective cohort studies indicate that midlife hypertension increases the risk of dementia, 4 suggesting that the blood pressure-lowering effects of antihypertensive drugs may reduce the incidence of dementia. Moreover, recent clinical studies and basic research have suggested several ways in which antihypertensive drugs can prevent target organ damage independently of their antihypertensive effect. In particular, the tissue reninangiotensin system (RAS) (the so-called local RAS) is involved not only in the vasculature but also in the brain. Accumulating evidence from large clinical trials suggests that blockade of the RAS by angiotensin (Ang) II type 1 (AT 1 ) receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors is more effective at inhibiting target organ (such as heart and kidney) damage than other hypertensive agents. 5 Here, we overview the accumulating evidence and suggest possible mechanisms by which ARBs prevent brain damage and dementia.

show abstract

Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation

Abstract: These results suggest that AT2 receptor stimulation has a protective effect on ischemic brain lesions, at least partly through the modulation of cerebral blood flow and superoxide production.

Cited by 233 publications

References 40 publications

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

Effects of angiotensin II receptor blockers on dementia

Contact Info

Product

Resources

About