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Alterations of signal transduction system in heart failure
1Department of Laboratory Medicine and Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Insights
Congestive heart failure (CHF) involves neurohumoral activation. This study found the cardiac renin-angiotensin (RA) system is upregulated in failing hearts, contributing to cardiac dysfunction.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Heart Failure Pathophysiology
Background:
- Congestive heart failure (CHF) is characterized by reduced cardiac contractility and compensatory neurohumoral activation.
- Chronic neurohumoral stimulation in CHF can desensitize cellular receptors and signaling pathways.
- Elevated inhibitory GTP-binding protein (Gi) and potentially reduced adenylyl cyclase activity are observed in failing hearts.
Purpose of the Study:
- To investigate changes in beta-adrenergic receptors (beta AR), GTP-binding proteins, catalytic proteins, and beta-adrenergic receptor kinase (beta ARK) in CHF.
- To examine angiotensinogen mRNA expression in failing human hearts.
- To assess the expression of components of the cardiac renin-angiotensin (RA) system in both diseased and non-diseased hearts.
Main Methods:
- Assessment of beta AR, GTP-binding protein, catalytic protein, and beta ARK levels.
- Analysis of angiotensinogen mRNA expression in atrial and ventricular tissues.
- Immunohistochemical studies for angiotensinogen localization.
- RNA detection for ACE, AT1 receptor, renin, and angiotensinogen (Ao) in ventricular muscles.
Main Results:
- Angiotensinogen mRNA is synthesized in human atrial and ventricular tissues, with stronger expression in the left ventricle endocardium and conduction system.
- Diseased hearts show widespread angiotensinogen immunoreactivity in the left ventricle.
- ACE and AT1 receptor RNA are present in non-diseased ventricular muscles, while renin and Ao mRNA are absent in the subendocardium.
- Renin and Ao mRNA are detected in the left ventricle of diseased hearts.
Conclusions:
- The cardiac renin-angiotensin (RA) system is synthesized within the human heart.
- Upregulation of cardiac RA system components, including angiotensinogen, renin, and Ao mRNA, is evident in failing hearts.
- These findings indicate a significant role for the cardiac RA system in the deterioration of cardiac function in congestive heart failure.
Abstract:
Congestive heart failure (CHF) patients share several similar features, such as reduced cardiac contractility and neurohumoral activation to compensate the impaired cardiac function. In CHF patients, the cardiac renin-angitensin (RA) system, receptors, GTP-binding proteins, and their effector molecules are inevitably exposed to chronically elevated neurohumoral stimulation. A widely recognized concept is that a chronic increase in such stimulation can desensitize target cell receptors and the post-receptor signal transducing pathway. Recently, reports of several studies have indicated that the inhibitory GTP-binding protein (Gi) can be increased in CHF patients and animal models. Although direct evidence for a change in catalytic protein of adenylyl cyclase has not been found, limited information has suggested a reduced catalytic activity in terminally failing hearts. In this paper, we have assessed the changes in beta AR, GTP-binding protein, catalytic protein and beta ARK. We also examined angiotensinogen mRNA expression in failing heart. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies revealed a stronger reaction in the endocardial layer of the human left ventricle than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. In the non-diseased heart, ACE and AT1 receptor RNA are present in ventricular muscles. Renin and Ao mRNA could not be detected in the subendocardium of non-diseased left ventricle, but both were present in the left ventricle of diseased hearts. These data indicate that the cardiac RA system plays an important role in the deterioration of cardiac function.