Angiotensin-(1–7) and the G Protein-Coupled Receptor Mas Are Key Players in Renal Inflammation

Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1–7) by interacting with the G protein-coupled receptor Mas may also have important biological activities

Prognostic Significance of Circulating Levels of Hepatocyte Growth Factor in Patients with Chagas’ Disease and Idiopathic Dilated Cardiomyopathy

Objectives: Hepatocyte growth factor (HGF) plays an important role in the improvement in cardiac function and remodeling in a variety of cardiovascular diseases. It is also a strong predictor of mortality in some heart failure (HF) patients. However, its prognostic value in patients with Chagas’ disease (CD) or idiopathic dilated cardiomyopathy (DCM) remains to be investigated. Methods and Results: In this prospective cohort study, HGF concentrations were measured in patients with CD (n = 91), DCM (n = 47), and control subjects (n = 25). While no difference was detected for patients with New York Heart Association class I–II, HGF was significantly increased in advanced HF patients (New York Heart Association class III–IV) in both CD and DCM groups, compared with healthy subjects. There was a strong correlation between HGF and left ventricular ejection fraction in CD patients. However, there was no correlation in patients with DCM. Despite its strong correlation with left ventricular ejection fraction in CD patients, HGF failed to predict mortality and necessity for heart transplant in both CD and DCM patients. Conclusions: Although HGF can be significantly increased in advanced HF patients with CD and DCM, its prognostic value for endpoints is minor. Therefore, the formerly described predictive power for HGF in HF might be restricted to specific etiologies of HF.Peer Reviewe

Angiotensin-(1–7) stimulates hematopoietic progenitor cells in vitro and in vivo

Effects of angiotensin (Ang)-(1–7), an AngII metabolite, on bone marrow-derived hematopoietic cells were studied. We identified Ang-(1–7) to stimulate proliferation of human CD34+ and mononuclear cells in vitro. Under in vivo conditions, we monitored proliferation and differentiation of human cord blood mononuclear cells in NOD/SCID mice. Ang-(1–7) stimulated differentially human cells in bone marrow and accumulated them in the spleen. The number of HLA-I+ and CD34+ cells in the bone marrow was increased 42-fold and 600-fold, respectively. These results indicate a decisive impact of Ang-(1–7) on hematopoiesis and its promising therapeutic potential in diseases requiring progenitor stimulation

Upregulation of bradykinin B1-receptor expression after myocardial infarction

To determine the influence of the myocardial infarction (MI) on bradykinin B1-receptor (B1R) regulation, we studied its expression in the left ventricle (LV) after MI. Rats were submitted to a permanent occlusion of the left coronary artery. Six hours, 24 h and 6 days after MI or after sham operation, left ventricular pressure (LVP) and dP/dt(max) were measured. LV-total RNA was extracted and B1R expression was analysed by a RNase-protection assay (each group n=6). LVP and dP/dt(max) were impaired at all time points after MI. Basal B1R expression was not detectable in controls. Six hours after MI, the B1R expression was upregulated and reached a maximum 24 h after MI (4 fold vs 6 h). Six days post-MI, B1R expression returned to levels found 6 h after MI. These data are the first demonstration for an induced myocardial B1R expression in an in vivo model of MI

Brain natriuretic peptide predicts survival in Chagas’ disease more effectively than atrial natriuretic peptide

Chagas’ disease, caused by the protozoan Trypanosoma cruzi, remains a leading cause of heart disease in Latin America. It is believed that approximately 20 million people are infected with this parasite. An acute phase follows the parasite infection and is characterised by an active infection, inflammation, and myocardial damage.1 Symptoms of chronic cardiomyopathy develop in 20–30% of previously asymptomatic individuals decades after initial infection. Severe congestive heart failure (CHF) is a common finding, and necropsies show notable dilation of all four cardiac chambers. Areas of extensive myocardial fibrosis and left ventricular apical aneurysms are common findings. Although atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are predictive of left ventricular hypertrophy and dysfunction, they respond differently, for example, to cardiac volume load in fetal circulation or diabetic cardiomyopathy. BNP has recently gained increased importance in the clinical diagnosis of cardiovascular diseases, and BNP guided treatment of CHF was found to reduce cardiovascular morbidity. The major studies and clinical trials on CHF have excluded Chagas patients. Thus the aim of our study was: firstly, to describe plasma ANP and BNP concentrations in Chagas patients compared to controls as a screening test for ventricular dysfunction; secondly, to investigate a possible correlation with the functional New York Heart Association (NYHA) class and left ventricular ejection fraction (LVEF) and the prognostic potency in Chagas’ disease; and thirdly, to compare peptide concentrations with those in patients with other dilated cardiomyopathies (DCM) in order to investigate this tool as a diagnostic marker for discriminating between the two types of heart failure

Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors

Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT1) and type 2 (AT2). In rodents, two AT1subtypes were identified (AT1aand AT1b). To determine receptor-specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT1subtypes. All combinations lacking AT1awere distinguished by reduced heart rate. AT1adeletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT1band/or AT2had no effect. However, the additional lack of AT1bin AT1a-deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the reninangiotensin system and to search for angiotensin II effects independent of AT1and AT2

Ang-(1–7) induces nuclear localization of p65 and p50 and proinflammatory cytokines in cultured mouse tubuloepithelial cells.

<p>(A) Growth arrested cells were treated with 10⁻⁷ mol/L Ang-(1–7) and AngII for 1 hour and p65 and p50 subunits were detected by an indirect immunostaining using a mouse FITC-labeled secondary antibody (green staining). Nuclei were stained with propidium iodure (in red). In the merge, the yellow staining shows nuclear localization of the NF-κB proteins after Ang-(1–7) stimulation. The results are representative of 3 independent observations done by confocal microscopy. (B) Growth arrested cells were incubated with 10⁻⁷ mol/L Ang-(1–7), AngII or TNFα for 1 hour. Thereafter, nuclear extracts were isolated and NF-κB activity was determined by binding assay with a labeled NF-κB oligonucleotide and analyzed by EMSA. Data are expressed as an n-fold increase vs. control cells, as mean±SEM of 4 experiments. *<i>P</i><0.05 vs. control. (C) Growth arrested cells were stimulated with 10⁻⁷ mol/L Ang-(1–7) or TNFα for 18 and 24 hours. Gene expression of MCP-1 and IL-6 was analyzed by real-time PCR. Results are expressed as mean±SEM of 4 experiments. *<i>P</i><0.05 vs. control.</p