Exercise training reduces cardiac angiotensin II levels and prevents cardiac dysfunction in a genetic model of sympathetic hyperactivity-induced heart failure in mice

2009 ◽  
Vol 105 (6) ◽  
Author(s):  
M. G. Pereira ◽  
J. C. B. Ferreira ◽  
C. R. Bueno ◽  
K. C. Mattos ◽  
K. T. Rosa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Exercise Training ◽  
Cardiac Dysfunction ◽  
Genetic Model ◽  
Sympathetic Hyperactivity

scholarly journals Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice

2008 ◽  
Vol 104 (1) ◽  
pp. 103-109 ◽  
Author(s):  
Alessandra Medeiros ◽  
Natale P. L. Rolim ◽  
Rodrigo S. F. Oliveira ◽  
Kaleizu T. Rosa ◽  
Katt C. Mattos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Cardiac Dysfunction ◽  
Ventricular Dysfunction ◽  
Exercise Intolerance ◽  
Calcium Handling ◽  
Plasma Norepinephrine ◽  
Sympathetic Hyperactivity ◽  
Preventive Cardiology ◽  
Significant Difference

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca2+ handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic α2A/α2C-adrenoceptor knockout (α2A/α2CARKO) mice with C57BL6/J genetic background (3–5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser2809-RyR, sarcoplasmic reticulum Ca2+ ATPase (SERCA2), Na+/Ca2+ exchanger (NCX), phospholamban (PLN), phospho-Ser16-PLN, and phospho-Thr17-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and α2A/α2CARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, α2A/α2CARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, α2A/α2CARKO mice displayed increased phospho-Ser16-PLN (76%) and phospho-Ser2809-RyR (49%). ET in α2A/α2CARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser16-PLN (30%) while it restored the expression of phospho-Ser2809-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca2+ handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

scholarly journals Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation

2021 ◽  
Vol 22 (18) ◽  
pp. 9883
Author(s):  
Joshua Abd Alla ◽  
Yahya F. Jamous ◽  
Ursula Quitterer
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Fatty Acid Synthase ◽  
Left Ventricular ◽  
At1 Receptor ◽  
Receptor Protein ◽  
Cardiac Lipid ◽  
Stearoyl Coa Desaturase ◽  
The Impact

Heart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (Scd1), in different experimental models of heart failure induced by advanced atherosclerosis, chronic pressure overload, and/or volume overload. Because the pathophysiological role of Scd1/SCD in heart failure is not clear, we investigated the impact of cardiac SCD upregulation through the generation of C57BL/6-Tg(MHCSCD)Sjaa mice with myocardium-specific expression of SCD. Echocardiographic examination showed that 4.9-fold-increased SCD levels triggered cardiac hypertrophy and symptoms of heart failure at an age of eight months. Tg-SCD mice had a significantly reduced left ventricular cardiac ejection fraction of 25.7 ± 2.9% compared to 54.3 ± 4.5% of non-transgenic B6 control mice. Whole-genome gene expression profiling identified up-regulated heart-failure-related genes such as resistin, adiponectin, and fatty acid synthase, and type 1 and 3 collagens. Tg-SCD mice were characterized by cardiac lipid accumulation with 1.6- and 1.7-fold-increased cardiac contents of saturated lipids, palmitate, and stearate, respectively. In contrast, unsaturated lipids were not changed. Together with saturated lipids, apoptosis-enhancing p53 protein contents were elevated. Imaging by autoradiography revealed that the heart-failure-promoting and membrane-spanning angiotensin II AT1 receptor protein of Tg-SCD hearts was significantly up-regulated. In transfected HEK cells, the expression of SCD increased the number of cell-surface angiotensin II AT1 receptor binding sites. In addition, increased AT1 receptor protein levels were detected by fluorescence spectroscopy of fluorescent protein-labeled AT1 receptor-Cerulean. Taken together, we found that SCD promotes cardiac dysfunction with overload of cardiotoxic saturated lipids and up-regulation of the heart-failure-promoting AT1 receptor protein.

scholarly journals Modulation of angiotensin II signaling following exercise training in heart failure

2015 ◽  
Vol 308 (8) ◽  
pp. H781-H791 ◽  
Author(s):  
Irving H. Zucker ◽  
Harold D. Schultz ◽  
Kaushik P. Patel ◽  
Hanjun Wang
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Exercise Training ◽  
Work Capacity ◽  
Current Therapy ◽  
Adrenergic Blockade ◽  
Ang Ii ◽  
Cellular Mechanisms ◽  
Consistent Finding ◽  
Mortality And Morbidity

Sympathetic activation is a consistent finding in the chronic heart failure (CHF) state. Current therapy for CHF targets the renin-angiotensin II (ANG II) and adrenergic systems. Angiotensin converting enzyme (ACE) inhibitors and ANG II receptor blockers are standard treatments along with β-adrenergic blockade. However, the mortality and morbidity of this disease is still extremely high, even with good medical management. Exercise training (ExT) is currently being used in many centers as an adjunctive therapy for CHF. Clinical studies have shown that ExT is a safe, effective, and inexpensive way to improve quality of life, work capacity, and longevity in patients with CHF. This review discusses the potential neural interactions between ANG II and sympatho-excitation in CHF and the modulation of this interaction by ExT. We briefly review the current understanding of the modulation of the angiotensin type 1 receptor in sympatho-excitatory areas of the brain and in the periphery (i.e., in the carotid body and skeletal muscle). We discuss possible cellular mechanisms by which ExT may impact the sympatho-excitatory process by reducing oxidative stress, increasing nitric oxide. and reducing ANG II. We also discuss the potential role of ACE2 and Ang 1–7 in the sympathetic response to ExT. Fruitful areas of further investigation are the role and mechanisms by which pre-sympathetic neuronal metabolic activity in response to individual bouts of exercise regulate redox mechanisms and discharge at rest in CHF and other sympatho-excitatory states.

Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training

2009 ◽  
Vol 106 (5) ◽  
pp. 1631-1640 ◽  
Author(s):  
Aline V. N. Bacurau ◽  
Maíra A. Jardim ◽  
Julio C. B. Ferreira ◽  
Luiz R. G. Bechara ◽  
Carlos R. Bueno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Exercise Tolerance ◽  
Muscular Atrophy ◽  
Exercise Intolerance ◽  
Muscle Morphology ◽  
Sympathetic Hyperactivity ◽  
Capillary Rarefaction

Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF), and several lines of evidence suggest that SH contributes to HF-induced skeletal myopathy. However, little is known about the influence of SH on skeletal muscle morphology and metabolism in a setting of developing HF, taking into consideration muscles with different fiber compositions. The contribution of SH on exercise tolerance and skeletal muscle morphology and biochemistry was investigated in 3- and 7-mo-old mice lacking both α2A- and α2C-adrenergic receptor subtypes (α2A/α2CARKO mice) that present SH with evidence of HF by 7 mo. To verify whether exercise training (ET) would prevent skeletal muscle myopathy in advanced-stage HF, α2A/α2CARKO mice were exercised from 5 to 7 mo of age. At 3 mo, α2A/α2CARKO mice showed no signs of HF and preserved exercise tolerance and muscular norepinephrine with no changes in soleus morphology. In contrast, plantaris muscle of α2A/α2CARKO mice displayed hypertrophy and fiber type shift (IIA → IIX) paralleled by capillary rarefaction, increased hexokinase activity, and oxidative stress. At 7 mo, α2A/α2CARKO mice displayed exercise intolerance and increased muscular norepinephrine, muscular atrophy, capillary rarefaction, and increased oxidative stress. ET reestablished α2A/α2CARKO mouse exercise tolerance to 7-mo-old wild-type levels and prevented muscular atrophy and capillary rarefaction associated with reduced oxidative stress. Collectively, these data provide direct evidence that SH is a major factor contributing to skeletal muscle morphological changes in a setting of developing HF. ET prevented skeletal muscle myopathy in α2A/α2CARKO mice, which highlights its importance as a therapeutic tool for HF.

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