Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Joseph Francis ◽  
Li Yu ◽  
Anuradha Guggilam ◽  
Srinivas Sriramula ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Neuronal Nos ◽  
The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

Abstract 813: Tnf-α Alters Superoxide And Nitric Oxide In The Brain Stem And Hypothalamus Contributes To Sympathoexcitation In Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Anuradha Guggilam ◽  
Li Yu ◽  
Philip J Ebenezer ◽  
Irving H Zucker ◽  
Joseph Francis
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
List Type ◽  
Tnf Α ◽  
The Brain

Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays an important role in the pathophysiology of cardiovascular disease. Recent evidence suggests that TNF-αinduced oxidative stress contributes to the development of cardiovascular disease. The present study examined the effect of TNF-αon the imbalance between nitric oxide (NO) and superoxide (O 2 . − ) production in the brain stem and hypothalamus and its contribution to enhanced sympathetic drive in mice with heart failure. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery in wild type (WT) and TNF knockout (TNF KO) mice. After 5 weeks, WT + MI mice exhibited left ventricular (LV) dilatation and a decrease in fractional shortening (%FS). Real time RT-PCR exhibited an increase in the mRNA expression for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the LV of WT + MI mice. The mRNA expression for nNOS was significantly reduced in the brain stem, while that of iNOS and Nox2 were elevated in the brain stem as well as hypothalamus of WT + MI mice. Plasma norepinephrine (NE) levels in WT + MI mice were greater in WT + MI mice than that in sham, or TNF KO + MI mice indicating that sympathetic drive was enhanced by TNF-αin this model. Conclusions: The present study shows that TNF-α contributes to left ventricular hypertrophy leading to ventricular dysfunction. TNF-αinduces the production of O 2 . − and modulates the production of nitric oxide in the brain stem of HF mice. TNF-αcontributes to sympatho-excitation in HF.

scholarly journals Cardioprotective role of myocardial endothelial nitric oxide synthase and serum nitric oxide induced by hexarelin in rats with myocardial infarction-induced heart failure

2021 ◽  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Left Ventricular ◽  
Nitric Oxide Level ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Background: Growth hormone-releasing peptides (GHRP) have been reported to possess cardioprotective properties; nonetheless, their mechanisms of action are still not very clear. Objectives: Some studies have suggested that modulation of endothelial nitric oxide synthase (eNOS) and the upregulation of nitric oxide (NO) are cardioprotective. Therefore, the present study strived to test the hypothesis that a potent GHRP analog (hexarelin) could increase serum nitric oxide level and regulate myocardial eNOS to alleviate the development of heart failure. Methods: Myocardial infarction-induced heart failure in rats was established by permanent coronary artery ligation. The sham group, control group, and heart failure group all received normal saline (100 µg/kg; SC BID; 30days), while the rats in the hexarelin treatment group were treated with hexarelin (100 µg/kg, SC BID, 30 days). The rats were tested for myocardial apoptosis, oxidative stress, left ventricular function, various molecular analyses, as well as pathological and structural myocardial changes. Results: Hexarelin treatment improved contractile function and attenuated myocardial histopathological damages, oxidative stress, fibrosis, as well as apoptosis. All these were accompanied by the upregulation of myocardial eNOS and an increase in serum NO concentration. Conclusion: As evidenced by the obtained results, the anti-cardiac failure capacity of hexarelinin in a rat model is mediated by an increase in serum nitric oxide level and the up-modulation of myocardial eNOS; therefore, they can be considered therapeutic targets against heart failure.

Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

1999 ◽  
Vol 5 (3) ◽  
pp. 79
Author(s):  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui ◽  
Tomomi Ide ◽  
Hideo Ustumi ◽  
Nobuhiro Suematsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

Abstract 337: Activation of Myocardial AMP-activated Protein Kinase by Metformin Prevents Progression of Heart Failure in Dogs; Involvement of eNOS Activation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hideyuki Sasaki ◽  
Hiroshi Asanuma ◽  
Masashi Fujita ◽  
Hiroyuki Takahama ◽  
Masanori Asakura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Cell Death ◽  
Protein Kinase ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Mrna Levels ◽  
Compound C ◽  
Amp Activated Protein Kinase

Background; Several studies have shown that metformin activates AMP-activated protein kinase (AMPK), which mediates potent cardioprotection against ischemia-reperfusion injury. AMPK is also activated in experimental failing myocardium, suggesting that activation of AMPK is beneficial for the pathophysiology of heart failure. We investigated whether metformin prevents oxidative stress-induced cell death in rat cardiomyocytes and attenuates the progression of heart failure in dogs. Methods and Results; The treatment with metformin (10 μmol/L) protected the rat cultured cardiomyocytes against cell death due to H 2 O 2 exposure (50 μmol/L) as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), TUNEL staining, and flow cytometry. These effects were blunted by an AMPK inhibitor, compound-C (20 μmol/L), suggesting that the activation of AMPK decreased the extent of apoptosis-induced cell death due to H 2 O 2 exposure. Continuous rapid ventricular pacing (230/min for 4 weeks) in dogs caused heart failure and the treatment with metformin (100 mg/kg/day PO, n=8) decreased left ventricular (LV) end-diastolic dimension (32.8±0.4 vs. 36.5±1.0 mm, p< 0.01) and pressure (11.8±1.1 vs. 22±0.9 mmHg, p< 0.01), and increased LV fractional shortening (18.6±1.8 vs. 9.6±0.7 %, p< 0.01) along with enhanced phosphorylation of AMPK and the decreased the number of TUNEL-positive cells of the LV myocardium compared with the vehicle group (n=8). Interestingly, metformin increased the protein and mRNA levels of endothelial nitric oxide synthase of the LV myocardium and plasma nitric oxide levels. Metformin improved the plasma insulin resistance without increased myocardial GLUT-4 translocation. Furthermore, the subcutaneous administration of AICAR (50 mg/kg/every other day), another AMPK activator mediated the equivalent effects to metformin, strengthening the pivotal role of AMPK in reduction of apoptosis and prevention of heart failure. Conclusions; Activation of myocardial AMPK attenuated the oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with eNOS activation. Thus, metformin or AICAR may be applicable as a novel therapy for heart failure.

Abstract 3295: De-induction of the Maladaptive Fetal Gene Program During Chronic Monotherapy with Metoprolol Succinate is Retained Following Withdrawal of Therapy in Dogs with Chronic Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Rasha Bazari ◽  
Sharad Rastogi ◽  
Valerio Zaca ◽  
Sidney Goldstein ◽  
Hani N Sabbah
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Lv Function ◽  
Metoprolol Succinate ◽  
Myosin Heavy Chain Isoform ◽  
Chronic Therapy ◽  
Lv Remodeling

Background: Chronic therapy with extended release metoprolol succinate (MET), a selective β1 adrenergic receptor blocker, improves left ventricular (LV) function and attenuates global LV remodeling in dogs with chronic heart failure (HF). We previously showed that chronic therapy with β-blockade results in de-induction of the fetal gene program (FGP) in LV myocardium of dogs with HF. In this study, we tested the hypothesis that in dogs with HF withdrawal of chronic MET does not lead to re-induction of FGP. Methods: Studies were performed in 17 intracoronary microembolization-induced HF dogs randomized to 3 months oral therapy with MET (100 mg, once daily, n=11) or no therapy at all (Controls, n=6). In dogs randomized to MET, 6 were sacrificed after 3 months of therapy and in the remaining 5, MET was withdrawn after 3 months of therapy and dogs were observed for 6 weeks after withdrawal of MET (MET-W) and then sacrificed. LV tissue was also obtained from 6 normal (NL) dogs for comparison. mRNA expression of the FGP genes namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), sarcoplasmic reticulum calcium ATPase (CAA), cardiac β-1 adren-ergic receptor (AR) and α-myosin heavy chain isoform (α-MHC) was measured using reverse transcriptase polymerase chain reaction (RT-PCR) and bands were quantified in densitometric units (du). Results: In Controls, mRNA expression of ANP and BNP increased and expression of CAA, β 1-AR and α-MHC decreased. Treatment with MET decreased expression of ANP and BNP and increased expression of CAA, β 1-AR and α-MHC. Except for α-MHC, the improvement in FGP seen during MET treatment was preserved in MET-W dogs. Conclusions: Withdrawal of MET is associated with sustained de-induction of the FGP in LV myocardium of dogs with HF. This observation supports the concept that chronic β-blockade therapy in HF confers lasting reversal of LV remodeling and molecular recovery of the failing myocardium.

scholarly journals Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure

2015 ◽  
Vol 309 (8) ◽  
pp. H1281-H1287 ◽  
Author(s):  
Edmund Cauley ◽  
Xin Wang ◽  
Jhansi Dyavanapalli ◽  
Ke Sun ◽  
Kara Garrott ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Brain Stem ◽  
Ventricular Hypertrophy ◽  
Cardiac Activity ◽  
Left Ventricular ◽  
Parasympathetic Activity ◽  
The Brain

Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases.

Atrial natriuretic peptide transcription, storage, and release in rats with myocardial infarction

1987 ◽  
Vol 253 (6) ◽  
pp. H1449-H1455 ◽  
Author(s):  
R. E. Mendez ◽  
J. M. Pfeffer ◽  
F. V. Ortola ◽  
K. D. Bloch ◽  
S. Anderson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Infarct Size ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mrna Levels ◽  
Atrial Natriuretic

To study the role of atrial natriuretic peptide (ANP) in chronic heart failure, ANP synthesis, storage, and release were examined by measuring atrial ANP messenger ribonucleic acid (mRNA) levels and atrial and plasma ANP concentrations in rats with myocardial infarction produced by coronary artery ligation. Three groups were defined as the following: 1) controls, sham-operated, or operated, but noninfarcted; 2) moderate infarcts, involving 5-30% of the left ventricular circumference; and 3) large infarcts (greater than or equal to 30%). In addition, to determine a possible modulation by dietary Na intake on ANP levels in heart failure, plasma immunoreactive ANP (iANP) levels were measured in rats with and without infarcts given low, regular, or high Na intake for 2 wk, by which time all groups were in neutral balance. Plasma iANP levels varied directly with increasing infarct and atrial sizes, irrespective of Na intake. In contrast, atrial ANP concentration varied inversely with increasing infarct size. The ANP mRNA content index, a measure of total atrial ANP mRNA, was significantly increased in rats with large infarcts compared with control rats. These results indicate that in rats with myocardial infarction, the severity of left ventricular dysfunction, as inferred from infarct size, but not chronic Na intake, is the primary determinant of the extent of activation of the ANP system. Elevated circulating ANP levels are maintained through enhanced atrial synthesis and release. ANP may thus play an important role in the hemodynamic and renal adaptations to chronic heart failure.

scholarly journals Scar and pulmonary expression and shedding of ACE in rat myocardial infarction

2002 ◽  
Vol 283 (1) ◽  
pp. H156-H164 ◽  
Author(s):  
Roger Gaertner ◽  
Fabrice Prunier ◽  
Monique Philippe ◽  
Liliane Louedec ◽  
Jean-Jacques Mercadier ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mrna Expression ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Converting Enzyme ◽  
Pulmonary Endothelium ◽  
Expression Activity ◽  
Ace Activity ◽  
Expression And Activity

We examined the topology of angiotensin-converting enzyme (ACE) mRNA expression, activity, and shedding in myocardial infarction-induced heart failure and sought to elucidate the source of the increased plasma ACE activity in this model. Three months after coronary ligature, lung, scar, and remaining viable left ventricular tissues were analyzed for ACE mRNA expression as well as tissue and solubilized ACE activity. ACE mRNA expression increased in the scar with respect to infarct severity, decreased in the lung, and remained unchanged in the left ventricle. ACE activity decreased in the lung and increased in the scar tissue and plasma. Shedding of ACE remained constant in the lung and increased in the scar. This study shows that ACE expression and activity is shifted from the pulmonary endothelium to the infarct scar tissue and that constancy of shedding in the lung and its increase in the scar are the source of the increased plasma ACE in congestive heart failure.

Overexpression of eNOS in brain stem reduces enhanced sympathetic drive in mice with myocardial infarction

2005 ◽  
Vol 289 (5) ◽  
pp. H2159-H2166 ◽  
Author(s):  
Koji Sakai ◽  
Yoshitaka Hirooka ◽  
Hideaki Shigematsu ◽  
Takuya Kishi ◽  
Koji Ito ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Brain Stem ◽  
Nucleus Tractus Solitarius ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
No Production ◽  
Ventricular Ejection Fraction ◽  
Intracisternal Injection ◽  
The Brain ◽  
Nnos Expression

Reduced nitric oxide (NO) in the brain might contribute to enhanced sympathetic drive in heart failure (HF). The aim of this study was to determine whether increased NO production induced by local overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarius (NTS) of the brain stem reduces the enhanced sympathetic drive in mice with HF. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. MI mice exhibited left ventricular dilatation and a reduced left ventricular ejection fraction. Urinary norepinephrine excretion in MI mice was greater than that in sham-operated mice, indicating that sympathetic drive was enhanced in this model. Thus this model has features that are typical of HF. Western blot analysis and immunohistochemical staining for neuronal NOS (nNOS) indicated that nNOS protein expression was significantly reduced in the brain stem of MI mice. MI mice had a significantly smaller increase in blood pressure evoked by intracisternal injection of NG-monomethyl-l-arginine than sham-operated mice. Adenoviral vectors encoding either eNOS (AdeNOS) or β-galactosidase (Adβgal) were transfected into the NTS to examine the effect of increased NO production in the NTS on the enhanced sympathetic drive in HF. After the gene transfer, urinary norepinephrine excretion was reduced in AdeNOS-transfected MI mice but not in Adβgal-transfected MI mice. These results indicate that nNOS expression in the brain stem, especially in the NTS, is reduced in the MI mouse model of HF, and increased NO production induced by overexpression of eNOS in the NTS attenuates the enhanced sympathetic drive in this model.

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