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Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular
G G Serneri1, M Boddi, I Cecioni
1Clinica Medica Generale e Cardiologia, University of Florence, Institute of Thoracic and Cardiovascular Surgery, University of Siena, Italy.
Insights
Cardiac angiotensin II (Ang II) generation increases with heart failure (HF) progression. Failing heart cells lose the ability to produce growth factors in response to Ang II, despite unchanged AT(1) receptor density on myocytes.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- The cardiac renin-angiotensin system (RAS) plays a crucial role in cardiovascular homeostasis.
- Dysregulation of cardiac RAS is implicated in the pathophysiology of heart failure (HF).
- Understanding Angiotensin II (Ang II) generation and its downstream effects in HF is vital.
Purpose of the Study:
- To investigate cardiac Ang II generation and its relationship with left ventricular function in patients with HF.
- To examine the expression and localization of cardiac RAS components in failing hearts.
- To assess the responsiveness of failing myocytes to Ang II stimulation.
Main Methods:
- Measurement of aorta-coronary sinus concentration gradients of endogenous angiotensins.
- Analysis of angiotensinogen and angiotensin-converting enzyme mRNA levels.
- Immunohistochemical detection of Ang II and binding studies for AT(1) and AT(2) receptors.
- Assessment of insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 synthesis in isolated myocytes.
Main Results:
- Cardiac Ang II generation significantly increased with HF progression, predicted by end-systolic wall stress.
- Angiotensinogen and ACE mRNA levels were elevated in HF hearts, with expression primarily in nonmyocyte cells.
- While AT(1) receptor density on failing myocytes remained unchanged, it was reduced on failing heart membranes. Failing myocytes lost the ability to synthesize IGF-I and ET-1 in response to Ang II.
Conclusions:
- HF progression is associated with increased cardiac Ang II formation.
- Cardiac AT(1) receptor density on myocytes does not change in HF, but is reduced on membranes.
- Failing myocytes exhibit impaired synthesis of IGF-I and ET-1 upon Ang II stimulation, indicating a functional deficit.
Abstract:
In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.