Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging

Silva, Ricardo A. Peña; Chu, Yi; Miller, Jordan D.; Mitchell, Ian; Penninger, Josef; Faraci, Frank M.; Heistad, Donald D.

doi:10.1161/strokeaha.112.667063

Cited by 104 publications

(72 citation statements)

References 45 publications

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“…Nevertheless, whether ACE2 activation improves peripheral insulin resistance is still unknown. Although ACE2 deficiency induces or exacerbates vascular inflammation, heart failure, atherosclerosis, and renal damage in pathological conditions (19,35,38,39,54,55), the EDRs in aortas and the capacity of ROS production in primary cultured mouse endothelial cells and the plasma Ang (1-7) level are not different between ACE2 wild-type and deficient mice on normal chow. Moreover, the pharmacological inhibition of ACE2-Ang (1-7) did not impair EDRs in aortas from normal mice.…”

Section: Discussionmentioning

confidence: 92%

“…In diabetic db/db mice, ACE2-Ang (1-7) upregulation prevents pancreatic beta-cell dysfunction and apoptosis (2) and improves renal function (37). By contrast, ACE2 deficiency leads to or aggravates vascular dysfunction (39,55), diabetic cardiomyopathy, and nephropathy (38,47). These studies indicate that the ACE2-Ang (1-7)-Mas axis of the RAS is vasoprotective, probably through reducing Ang II production or acting against Ang II-stimulated oxidative stress and vascular inflammation.…”

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confidence: 99%

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Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

Zhang

Liu

Luo

et al. 2015

Antioxidants & Redox Signaling

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Aims: Angiotensin-converting enzyme 2 (ACE2)-angiotensin (1-7) [Ang (1-7)]-Mas constitutes the vasoprotective axis and is demonstrated to antagonize the vascular pathophysiological effects of the classical reninangiotensin system. We sought to study the hypothesis that upregulation of ACE2-Ang (1-7) signaling protects endothelial function through reducing oxidative stress that would result in beneficial outcome in diabetes. Results: Ex vivo treatment with Ang (1-7) enhanced endothelium-dependent relaxation (EDR) in renal arteries from diabetic patients. Both Ang (1-7) infusion via osmotic pump (500 ng/kg/min) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection (10 9 pfu/mouse) rescued the impaired EDR and flow-mediated dilatation (FMD) in db/db mice. Diminazene aceturate treatment (15 mg/kg/day) activated ACE2, increased the circulating Ang (1-7) level, and augmented EDR and FMD in db/db mouse arteries. In addition, activation of the ACE2-Ang (1-7) axis reduced reactive oxygen species (ROS) overproduction determined by dihydroethidium staining, CM-H 2 DCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortas and also in high-glucose-treated endothelial cells. Pharmacological benefits of ACE2-Ang (1-7) upregulation on endothelial function were confirmed in ACE2 knockout (ACE2 KO) mice both ex vivo and in vitro. Innovation: We elucidate that the ACE2-Ang (1-7)-Mas axis serves as an important signal pathway in endothelial cell protection in diabetic mice, especially in diabetic human arteries. Conclusion: Endogenous ACE2-Ang (1-7) activation or ACE2 overexpression preserves endothelial function in diabetic mice through increasing nitric oxide bioavailability and inhibiting oxidative stress, suggesting the therapeutic potential of ACE2-Ang(1-7) axis activation against diabetic vasculopathy. Antioxid. Redox Signal. 23, 880-892.

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

Zhang

Liu

Luo

et al. 2015

Antioxidants & Redox Signaling

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“…Preventing cerebrovascular abnormalities in the elderly has important clinical implications for both stroke treatment and stroke prevention [1]. Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy and cognitive decline [1,2,5]. ROS levels are important determinants of age-related cerebrovascular endothelial performance including ischemic stroke vulnerability [5,19].…”

Section: Discussionmentioning

confidence: 99%

“…Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy and cognitive decline [1,2,5]. ROS levels are important determinants of age-related cerebrovascular endothelial performance including ischemic stroke vulnerability [5,19]. ROS removal is an effective treatment for cerebrovascular diseases; however, exogenous antioxidant supplements have not had promising effects on ROS-related vascular diseases [27,28].…”

Section: Discussionmentioning

confidence: 99%

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Dietary Curcumin Ameliorates Aging-Related Cerebrovascular Dysfunction through the AMPK/Uncoupling Protein 2 Pathway

Zhang

Wang

et al. 2013

Cell Physiol Biochem

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Background/Aims: Age-related cerebrovascular dysfunction contributes to stroke, cerebral amyloid angiopathy, cognitive decline and neurodegenerative diseases. One pathogenic mechanism underlying this effect is increased oxidative stress. Up-regulation of mitochondrial uncoupling protein 2 (UCP2) plays a crucial role in regulating reactive oxygen species (ROS) production. Dietary patterns are widely recognized as contributors to cardiovascular and cerebrovascular disease. In this study, we tested the hypothesis that dietary curcumin, which has an antioxidant effect, can improve aging-related cerebrovascular dysfunction via UCP2 up-regulation. Methods: The 24-month-old male rodents used in this study, including male Sprague Dawley (SD) rats and UCP2 knockout (UCP2-/-) and matched wild type mice, were given dietary curcumin (0.2%). The young control rodents were 6-month-old. Rodent cerebral artery vasorelaxation was detected by wire myograph. The AMPK/UCP2 pathway and p-eNOS in cerebrovascular and endothelial cells were observed by immunoblotting. Results: Dietary curcumin administration for one month remarkably restored the impaired cerebrovascular endothelium-dependent vasorelaxation in aging SD rats. In cerebral arteries from aging SD rats and cultured endothelial cells, curcumin promoted eNOS and AMPK phosphorylation, up-regulated UCP2 and reduced ROS production. These effects of curcumin were abolished by either AMPK or UCP2 inhibition. Chronic dietary curcumin significantly reduced ROS production and improved cerebrovascular endothelium-dependent relaxation in aging wild type mice but not in aging UCP2-/- mice. Conclusions: Curcumin improves aging-related cerebrovascular dysfunction via the AMPK/UCP2 pathway.

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Neurological damages in COVID‐19 patients: Mechanisms and preventive interventions

Sarkar

Karmakar

Basu

et al. 2023

MedComm

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a novel coronavirus, causes coronavirus disease 2019 (COVID‐19) which led to neurological damage and increased mortality worldwide in its second and third waves. It is associated with systemic inflammation, myocardial infarction, neurological illness including ischemic strokes (e.g., cardiac and cerebral ischemia), and even death through multi‐organ failure. At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia‐driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS‐CoV‐2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. Suppression of immunological machinery and inhibition of ROS play an important role in neurological disturbances. So, COVID‐19 associated damage to the central nervous system, patients need special care to prevent multi‐organ failure at later stages of disease progression. Here in this review, we are selectively discussing these issues and possible antioxidant‐based prevention therapies for COVID‐19‐associated neurological damage that leads to multi‐organ failure.

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Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging

Cited by 104 publications

References 45 publications

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

Dietary Curcumin Ameliorates Aging-Related Cerebrovascular Dysfunction through the AMPK/Uncoupling Protein 2 Pathway

Neurological damages in COVID‐19 patients: Mechanisms and preventive interventions

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