Changes in skeletal muscle SR Ca2+ pump in congestive heart failure due to myocardial infarction are prevented by angiotensin II blockade

2004 ◽  
Vol 82 (7) ◽  
pp. 438-447 ◽  
Author(s):  
Kanu R Shah ◽  
Pallab K Ganguly ◽  
Thomas Netticadan ◽  
Amarjit S Arneja ◽  
Naranjan S Dhalla
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Congestive Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Muscle Fatigue ◽  
Ace Inhibitors ◽  
Renin Angiotensin System ◽  
Exercise Intolerance ◽  
Angiotensin System

In order to understand the mechanisms of exercise intolerance and muscle fatigue, which are commonly observed in congestive heart failure, we studied sarcoplasmic reticulum (SR) Ca2+-transport in the hind-leg skeletal muscle of rats subjected to myocardial infarction (MI). Sham-operated animals were used for comparison. On one hand, the maximal velocities (Vmax) for both SR Ca2+-uptake and Ca2+-stimulated ATPase activities in skeletal muscle of rats at 8 weeks of MI were higher than those of controls. On the other hand, the Vmax values for both SR Ca2+-uptake and Ca2+-stimulated ATPase activities were decreased significantly at 16 weeks of MI when compared with controls. These alterations in Ca2+-transport activities were not associated with any change in the affinity (1/Ka) of the SR Ca2+-pump for Ca2+. Furthermore, the stimulation of SR Ca2+-stimulated ATPase activity by cyclic AMP-dependent protein kinase was not altered at 8 or 16 weeks of MI when compared with the respective control values. Treatment of 3-week infarcted animals with angiotensin-converting enzyme (ACE) inhibitors such as captopril, imidapril, and enalapril or an angiotensin receptor (AT1R) antagonist, losartan, for a period of 13 weeks not only attenuated changes in left ventricular function but also prevented defects in SR Ca2+-pump in skeletal muscle. These results indicate that the skeletal muscle SR Ca2+-transport is altered in a biphasic manner in heart failure due to MI. It is suggested that the initial increase in SR Ca2+-pump activity in skeletal muscle may be compensatory whereas the depression at late stages of MI may play a role in exercise intolerance and muscle fatigue in congestive heart failure. Furthermore, the improvements in the skeletal muscle SR Ca2+-transport by ACE inhibitors may be due to the decreased activity of renin-angiotensin system in congestive heart failure.Key words: skeletal muscle, sarcoplasmic reticulum, Ca2+-transport, SR Ca2+-pump, congestive heart failure, renin-angiotensin system.

scholarly journals A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

2017 ◽  
Vol 312 (5) ◽  
pp. H968-H979 ◽  
Author(s):  
Neeru M. Sharma ◽  
Shyam S. Nandi ◽  
Hong Zheng ◽  
Paras K. Mishra ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Paraventricular Nucleus ◽  
Renin Angiotensin System ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

Skeletal Muscle Sarcoplasmic Reticulum Ca 2+ -ATPase Gene Expression in Congestive Heart Failure

1997 ◽  
Vol 81 (5) ◽  
pp. 703-710 ◽  
Author(s):  
David G. Peters ◽  
Heather L. Mitchell ◽  
Sylvia A. McCune ◽  
Sonhee Park ◽  
Jay H. Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Congestive Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Atpase Gene

Brain “ouabain” and angiotensin II contribute to cardiac dysfunction after myocardial infarction

1999 ◽  
Vol 277 (5) ◽  
pp. H1786-H1792 ◽  
Author(s):  
Frans H. H. Leenen ◽  
Baoxue Yuan ◽  
Bing S. Huang
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Renin Angiotensin System ◽  
Volume Overload ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Fab Fragments ◽  
The Brain

In chronic heart failure (CHF), sympathetic activity increases in parallel with the impairment of left ventricle (LV) function, and sympathetic hyperactivity has been postulated to contribute to the progression of heart failure. In the brain, compounds with ouabain-like activity (“ouabain,” for brevity) and the renin-angiotensin system contribute to sympathetic hyperactivity in rats with CHF after myocardial infarction (MI). In the present studies, we assessed whether, in rats, chronic blockade of brain “ouabain” or the brain renin-angiotensin system inhibits the post-MI LV dysfunction. In rats, an MI was induced by acute coronary artery ligation. At either 0.5 or 4 wk post-MI, chronic treatment with Fab fragments for blocking brain “ouabain” or with losartan for blocking brain AT1 receptors was started and continued until 8 wk post-MI using osmotic minipumps connected to intracerebroventricular cannulas. At 8 wk post-MI, in conscious rats, LV pressures were measured at rest and in response to volume and pressure overload, followed by LV passive pressure-volume curves in vitro. At 8 wk post-MI, control MI rats exhibited clear increases in LV end-diastolic pressure (LVEDP) at rest and in response to pressure and volume overload. LV pressure-volume curves in vitro showed a marked shift to the right. Intravenous administration of the Fab fragments or losartan at rates used for central blockade did not affect these parameters. In contrast, chronic central blockade with either Fab fragments or losartan significantly lowered LVEDP at rest (only in 0.5- to 8-wk groups) and particularly in response to pressure or volume overload. LV dilation, as assessed from LV pressure-volume curves, was also significantly inhibited. These results indicate that chronic blockade of brain “ouabain” or brain AT1 receptors substantially inhibits development of LV dilation and dysfunction in rats post-MI.

Modification of the pulmonary renin–angiotensin system and lung structural remodelling in congestive heart failure

2006 ◽  
Vol 111 (3) ◽  
pp. 217-224 ◽  
Author(s):  
Frederic Lefebvre ◽  
Annick Préfontaine ◽  
Angelino Calderone ◽  
Alexandre Caron ◽  
Jean-François Jasmin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Renin Angiotensin System ◽  
At1 Receptor ◽  
Receptor Expression ◽  
Coronary Artery Ligation ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Lung Remodelling

Lung structural remodelling, characterized by myofibroblast proliferation and collagen deposition, contributes to impaired functional capacity in CHF (congestive heart failure). As the lung is the primary site for the formation of Ang II (angiotensin II), local modifications of this system could contribute to lung remodelling. Rats with CHF, induced following myocardial infarction (MI) via coronary artery ligation, were compared with sham-operated controls. The MI group developed lung remodelling as confirmed by morphometric measurements and immunohistochemistry. Pulmonary Ang II concentrations increased more than 6-fold (P<0.01), and AT1 (Ang II type 1) receptor expression was elevated by 3-fold (P<0.01) with evidence of distribution in myofibroblasts. AT2 (Ang II type 2) receptor expression was unchanged. In isolated lung myofibroblasts, AT1 and AT2 receptors were expressed, and Ang II stimulated proliferation as measured by [3H]thymidine incorporation. In normal rats, chronic intravenous infusion of Ang II (0.5 mg·kg−1 of body weight·day−1) for 28 days significantly increased mean arterial pressure (P<0.05), without pulmonary hypertension, lung remodelling or a change in AT1 receptor expression. We conclude that there is a modification of the pulmonary renin–angiotensin system in CHF, with increased Ang II levels and AT1 receptor expression on myofibroblasts. Although this may contribute to lung remodelling, the lack of effect of increased plasma Ang II levels alone suggests the importance of local pulmonary Ang II levels combined with the effect of other factors activated in CHF.

A SHORT HISTORY OF THE RENIN-ANGIOTENSIN SYSTEM

2009 ◽  
Vol 38 (1) ◽  
pp. 8-12 ◽  
Author(s):  
Rajko Igic
Keyword(s):  
Heart Failure ◽  
Ace Inhibitors ◽  
Body Fluid ◽  
Local Level ◽  
Renin Angiotensin System ◽  
Short History ◽  
Angiotensin System ◽  
Technological Advances ◽  
History Of ◽  
Hormone System

The renin-angiotesin system (RAS) was initially recognized as the body’s most powerful hormone system for controlling body fluid volumes and arterial pressure. Then, it was shown that the RAS operates at both systemic (endocrine) and tissue (local) level. Development of ACE inhibitors proved that the RAS is effective in controlling hypertension and heart failure, and in preventing the vascular injury in chronic diseases. The success of ACE inhibitors stimulated research into inhibitors of other components of this system. Major challenge in the future will be to utilize the technological advances for better understanding the physiology and pathophysiology of the RAS, and to develop new therapeutic paradigms. This article briefly reviews the research in this area, and points out the seventieth anniversary of angiotensin.

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