scholarly journals Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction

2009 ◽  
Vol 296 (1) ◽  
pp. R1-R8 ◽  
Author(s):  
Timothy E. Lindley ◽  
David W. Infanger ◽  
Mark Rishniw ◽  
Yi Zhou ◽  
Marc F. Doobay ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Central Nervous System ◽  
Nervous System ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Myocardial Function ◽  
Critical Role ◽  
Coronary Artery Ligation ◽  
Control Vector

Dysregulation in central nervous system (CNS) signaling that results in chronic sympathetic hyperactivity is now recognized to play a critical role in the pathogenesis of heart failure (HF) following myocardial infarction (MI). We recently demonstrated that adenovirus-mediated gene transfer of cytoplasmic superoxide dismutase (Ad-Cu/ZnSOD) to forebrain circumventricular organs, unique sensory structures that lack a blood-brain barrier and link peripheral blood-borne signals to central nervous system cardiovascular circuits, inhibits both the MI-induced activation of these central signaling pathways and the accompanying sympathoexcitation. Here, we tested the hypothesis that this forebrain-targeted reduction in oxidative stress translates into amelioration of the post-MI decline in myocardial function and increase in mortality. Adult C57BL/6 mice underwent left coronary artery ligation or sham surgery along with forebrain-targeted gene transfer of Ad-Cu/ZnSOD or a control vector. The results demonstrate marked MI-induced increases in superoxide radical formation in one of these forebrain regions, the subfornical organ (SFO). Ad-Cu/ZnSOD targeted to this region abolished the increased superoxide levels and led to significantly improved myocardial function compared with control vector-treated mice. This was accompanied by diminished levels of cardiomyocyte apoptosis in the Ad-Cu/ZnSOD but not the control vector-treated group. These effects of superoxide scavenging with Ad-Cu/ZnSOD in the forebrain paralleled increased post-MI survival rates compared with controls. This suggests that oxidative stress in the SFO plays a critical role in the deterioration of cardiac function following MI and underscores the promise of CNS-targeted antioxidant therapy for the treatment of MI-induced HF.

scholarly journals PO-173 The Effects of Interval Exercise on oxidative stress and Smyd1-related myocardial hypertrophy in Rats with Myocardial Infarction

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Qiaoqin Liang ◽  
Mengxin Cai ◽  
Jiaqi Zhang ◽  
Zhenjun Tian
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Stress Level ◽  
Exercise Group ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Interval Exercise ◽  
Oxidative Stress Level ◽  
Sarcomere Assembly

Objective This study was carried out to investigate interval exercise on Smyd1 expression and F-actin sarcomere assembly in non-infarcted myocardium of normal and myocardial infarction(MI) rats and its possible mechanism. Methods Male SD rats were randomly divided into normal control group (C), normal interval exercise group (CE), sham-operated group (S), MI group (MI), MI with interval exercise group (ME) and MI with ROS Tempol group (MT), n=10. MI model was established by left anterior descending coronary artery ligation. Interval exercise was carried out on a small animal treadmill. MT group was given an oral solution of Tempol (2mmol/L). Hemodynamics was performed to evaluate cardiac function. HE and Masson staining were used to analyze the cross-sectional area (CSA) of cardiomyocytes and collagen volume fraction, respectively. T-SOD and MDA kits were used to detect oxidative stress. H9C2 cells were treated with H2O2. Immunofluorescence staining was used to determine Smyd1 expression and F-actin sarcomere assembly. RT-qPCR and Western blotting were used to detect the gene or protein expression of Smyd1, Trx1, Hsp90, MuRF1, cTnI, α-actinin and BNP. Results Smyd1, Trx1, Hsp90, MuRF1 and BNP expression in the peri-infarcted area were up-regulated, but cTnI and α-actinin expression and F-actin assembly were decreased. The cardiac function was reduced. Both interval exercise and Tempol intervention significantly increase the CSA and expression of Smyd1, Trx1, cTnI and α-actinin, improve the antioxidation capacity and F-actin sarcomere assembly and cardiac function, reduce the expression of Hsp90, MuRF1, BNP and ROS level, and inhibit the fibrosis of myocardium. The oxidative stress level was closely related to the Smyd1 expression. Improvement of cardiac function were correlated with Smyd1 expression. H2O2 can induce oxidative stress injuries of H9C2, and its closely related to cardiomyocytes oxidative stress level and Smyd1 expression. Conclusions Interval exercise could promote antioxidant capability and physiological cardiomyocyte hypertrophy, regulate the expression of Smyd1, Hsp90 and MuRF1 in infarcted heart; so as to improve the cardiac function. Smyd1 may participate in pathologic hypertrophy of cardiomyocytes caused by oxidative stress.

Central mineralocorticoid receptor blockade decreases plasma TNF-α after coronary artery ligation in rats

2003 ◽  
Vol 284 (2) ◽  
pp. R328-R335 ◽  
Author(s):  
Joseph Francis ◽  
Robert M. Weiss ◽  
Alan Kim Johnson ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Central Nervous System ◽  
Nervous System ◽  
Mineralocorticoid Receptor ◽  
Critical Role ◽  
Evaluation Study ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Tnf Α ◽  
The Central Nervous System

The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3rd cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-α (TNF-α) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-α levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-α release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-α production.

Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure

2001 ◽  
Vol 281 (5) ◽  
pp. H2241-H2251 ◽  
Author(s):  
Joseph Francis ◽  
Robert M. Weiss ◽  
Shun-Guang Wei ◽  
Alan Kim Johnson ◽  
Terry G. Beltz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Central Nervous System ◽  
Nervous System ◽  
Volume Regulation ◽  
Critical Role ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Water Excretion ◽  
Beneficial Effects ◽  
The Central Nervous System

The mineralocorticoid (MC) receptor antagonist spironolactone (SL) improves morbidity and mortality in patients with congestive heart failure (CHF). We tested the hypothesis that the central nervous system actions of SL contribute to its beneficial effects. SL (100 ng/h for 28 days) or ethanol vehicle (VEH) was administered intracerebroventricularly or intraperitoneally to rats with CHF induced by coronary artery ligation (CL) and to SHAM-operated controls. The intracerebroventricular SL treatment prevented the increase in sodium appetite and the decreases in sodium and water excretion observed within a week of CL in VEH-treated CHF rats. Intraperitoneal SL also improved volume regulation in the CHF rats, but only after 3 wk of treatment. Four weeks of SL treatment, either intracerebroventricularly or intraperitoneally, ameliorated both the increase in sympathetic drive and the impaired baroreflex function observed in VEH-treated CHF rats. These findings suggest that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.

Heterogeneity and Proliferative and Differential Regulators of NG2-glia in Physiological and Pathological States

2020 ◽  
Vol 27 (37) ◽  
pp. 6384-6406 ◽  
Author(s):  
Zuo Zhang ◽  
Hongli Zhou ◽  
Jiyin Zhou
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Physiological State ◽  
Critical Role ◽  
Adult Brain ◽  
Pathological State ◽  
Peripheral Neurons ◽  
Neuronal Synapses ◽  
The Central Nervous System ◽  
Rapid Modulation

NG2-glia, also called Oligodendrocyte Precursor Cells (OPCs), account for approximately 5%-10% of the cells in the developing and adult brain and constitute the fifth major cell population in the central nervous system. NG2-glia express receptors and ion channels involved in rapid modulation of neuronal activities and signaling with neuronal synapses, which have functional significance in both physiological and pathological states. NG2-glia participate in quick signaling with peripheral neurons via direct synaptic touches in the developing and mature central nervous system. These distinctive glia perform the unique function of proliferating and differentiating into oligodendrocytes in the early developing brain, which is critical for axon myelin formation. In response to injury, NG2-glia can proliferate, migrate to the lesions, and differentiate into oligodendrocytes to form new myelin sheaths, which wrap around damaged axons and result in functional recovery. The capacity of NG2-glia to regulate their behavior and dynamics in response to neuronal activity and disease indicate their critical role in myelin preservation and remodeling in the physiological state and in repair in the pathological state. In this review, we provide a detailed summary of the characteristics of NG2-glia, including their heterogeneity, the regulators of their proliferation, and the modulators of their differentiation into oligodendrocytes.

Brain organoids: a promising model to assess oxidative stress‐induced Central Nervous System damage

2021 ◽  
Author(s):  
Foluwasomi A. Oyefeso ◽  
Alysson R. Muotri ◽  
Christopher G. Wilson ◽  
Michael J. Pecaut
Keyword(s):  
Oxidative Stress ◽  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Damage

Abstract 17166: Myeloid-specific Deletion of the Glucocorticoid Receptor Increases Mitochondrial Oxidative Stress and Impairs Wound Healing After Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jonas Neuser ◽  
Daniela Fraccarollo ◽  
Jan P Tuckermann ◽  
Paolo Galuppo ◽  
Johann Bauersachs
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Wound Healing ◽  
Glucocorticoid Receptor ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Myeloid Cells ◽  
Coronary Artery Ligation ◽  
Mitochondrial Oxidative Stress ◽  
Specific Deletion

Background: Glucocorticoid administration impairs ischemic wound healing by inhibiting inflammation and angiogenesis via a glucocorticoid receptor (GR)-mediated transcriptional response. However, there are also apparently contradictory reports claiming protective effects of glucorticoid administration after myocardial infarction (MI). We investigated the role of the GR in myeloid cells for infarct wound healing, using GR deficient mice (GRLysMCre). Methods and Results: MI was induced by permanent left coronary artery ligation in GRflox (wild-type [WT] controls) and GRLysMCre mice. The 7-day mortality was significantly lower in WT compared with GRLysMCre mice. At 7 days post MI, GRLysMCre mice exhibited significantly enhanced thinning and dilatation of the infarcted wall, LV chamber enlargement and functional deterioration. This was associated with altered granulation tissue formation and impaired neoangiogenesis at the site of ischemic injury. Multicolor flow cytometric analysis and immunohistochemical studies revealed at the 2nd day post infarction less infiltrating mononuclear cells [CD11bhigh and (CD49b, NK1.1, B220, CD90, Ly6G)low] in the healing myocardium of GRLysMCre mice. Mononuclear cells were identified as monocytes (F4/80, I-Ab, CD11c)low and as macrophages/dendritic cells (F4/80, I-Ab, CD11c)high. Monocytes lacking GR, isolated from peripheral blood and spleen by magnetic-activated cell sorting 1 day after MI, displayed reduced migration capacity and increased superoxide anion production in mitochondria, which was detected by HPLC-electrochemical analysis of Mito-2-hydroxy-E+. Moreover, at day 2 and 3 we found enhanced cellular and mitochondrial oxidative stress in the healing myocardium of GRLysMCre mice. Conclusions: Myeloid-specific deletion of the GR increasing mitochondrial oxidative stress alters wound healing and promotes infarct expansion. Our results suggest that the GR in myeloid cells play a crucial role during cardiac repair after myocardial infarction.

Abstract 103: ACE2 Overexpression Prevents DOCA-Salt Hypertension by Modulating Oxidative Stress and Nitric Oxide in the Central Nervous System

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Srinivas Sriramula ◽  
Huijing Xia ◽  
Eric Lazartigues
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Central Nervous System ◽  
Nervous System ◽  
Nadph Oxidase ◽  
Salt Treatment ◽  
Salt Hypertension ◽  
The Central Nervous System ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Elevated reactive oxygen species (ROS) in the central nervous system (CNS) through NADPH oxidase and diminished Nitric oxide (NO) levels are involved in the pathogenesis of hypertension. We previously reported that central Angiotensin Converting Enzyme 2 (ACE2) overexpression prevents the development of hypertension induced by DOCA-salt in a transgenic mouse model (syn-hACE2; SA) with human ACE2 targeted selectively to neurons in the CNS. While baseline blood pressure (BP; telemetry) was not different among genotypes, DOCA-salt treatment (1mg/g body wt DOCA, 1% saline in drinking water for 3 weeks) resulted in significantly lower BP level in SA mice (122 ±3 mmHg, n=12) compared to non-transgenic (NT) littermates (138 ±3 mmHg, n=8). To elucidate the mechanisms involved in this response, we investigated the paraventricular nucleus (PVN) expression of Nox-2 (catalytic subunit of NADPH oxidase), 3-nitrotyrosine, and endothelial nitric oxide synthase (eNOS) and anti-oxidant enzymes superoxide dismutase (SOD) and catalase in the hypothalamus. DOCA-salt treatment resulted in decreased catalase (95.2 ±5.6 vs. 113.8 ±17.6 mmol/min/ml, p<0.05) and SOD (4.1 ±0.4 vs. 5.9 ±0.2 U/ml, p<0.01) activities in hypothalamic homogenates of NT mice, which was prevented by ACE2 overexpression (141.8 ±9.9 vs. 142.1 ±9.2 mmol/min/ml and 5.9 ±0.3 vs. 7.9 ±0.2 U/ml, respectively). NT mice treated with DOCA-salt showed increased oxidative stress as indicated by increased expression of Nox-2 (61 ±5 % increase, n=9, p<0.001 vs. NT) and 3-nitrotyrosine (89 ±32 % increase, n=9, p<0.01 vs. NT) in the PVN which was attenuated in SA mice. Furthermore, DOCA-salt hypertension resulted in decreased phosphorylation of eNOS-ser1177 in the PVN (33 ±5 % decrease, n=9, p<0.05 vs NT) and this decrease was prevented by ACE2 overexpression. Taken together, these data provide evidence that brain ACE2 regulates the balance between NO and ROS levels, thereby preventing the development of DOCA-salt hypertension.

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