Exploration of Medicine

Special Issue Topic

Angiotensins—A Century of Progress

Submission Deadline: December 31, 2020

Guest Editors

Dr. Carlos M. Ferrario E-Mail

Professor, General Surgery, Wake Forest School of Medicine, Winston-Salem, USA

Research Keywords: biochemical physiology of the renin angiotensin aldosterone system; neurohormonal regulation of blood pressure, essential hypertension and its mechanisms

Dr. Leanne Groban E-Mail

Professor, Anesthesiology, Wake Forest School of Medicine, Winston-Salem, USA

Research Keywords: sex differences in the pathophysiology of cardiovascular disease; aging and diastolic dysfunction; women’s heart health; diabetes and menopause

About the Special Issue

“The history of hypertension is both long and short”, so it was stated in the Preface to Angiotensin, Angiotensin, a book edited by Irvine H Page and F. Merlin Bumpus in 1974. Sixty-six years of continuous progress since the research of Skeggs et al. (PMCID: PMC2136385) isolation of angiotensin, the importance of this hormone, a product of the humoral system conceptualized as the renin angiotensin aldosterone system (RAAS) are pillars sustaining the development and applicability of medicines having a definitive impact in human disease, above and beyond their applicability to the treatment of diseases of the heart and the blood vessels. The multiplicity of the actions of the peptide hormones expressed within the RAAS continues to shed new light into human biology, tissue homeostasis, and the development of chronic non-communicable diseases. To celebrate these accomplishments and provide a forward look to RAAS participation in human disease, this special issue will highlight the major contributions to the understanding of the functions of angiotensins not only within and beyond its applicability to control of tissue perfusion, organ metabolic processes, inflammation, innate immunity, and fetal programming. And this issue welcomes diverse types of articles, including Original Article, Review, Meta-analysis, Systematic Review, Case Report, and Commentary.
The Editors believe that this special issue of Exploration of Medicine will allow the scientific community to reflect how far we have advanced in the frontiers of knowledge, where accepted knowledge of the system may need revision, and target the new frontiers of discovery in reaching ultimate knowledge of how hormones act to both regulate and dysregulate body homeostasis.

Keywords: angiotensins, renin, angiotensinogen, heart diseases, vascular diseases, stroke, heart failure, chronic kidney disease, pregnancy, fetal programming, age-related mobility/disability, sepsis, surgery/anesthesia-related hypotension, sex differences

Published Articles

Open Access

Original Article

High salt induced augmentation of angiotensin II mediated hypertension is associated with differential expression of tumor necrosis factor-alpha receptors in the kidney
Aim: Chronic high salt (HS) intake causes minimal changes in blood pressure (BP) but it induces augmented hypertensive response to angiotensin II (AngII) administration in rodents. The mechanism [...] Read more.

Aim:

Chronic high salt (HS) intake causes minimal changes in blood pressure (BP) but it induces augmented hypertensive response to angiotensin II (AngII) administration in rodents. The mechanism of this augmentation is not clearly understood. As tumor necrosis factor-alpha (TNF-α) induces natriuresis by activating TNF-α receptor type 1 (TNFR1) but not type 2 (TNFR2), we hypothesize that TNFR1 activity is reduced when HS is given in combination of AngII that leads to enhanced sodium retention and thus, causing augmented hypertension. The aim of this study is to examine the responses to chronic HS intake and AngII administration on the renal tissue protein expressions of TNFR1 and TNFR2 in mice.

Methods:

Different groups of mice (n = 6–7 in each group) chronically treated with or without AngII (25 ng/min; implanted minipump) for 4 weeks which were fed either normal salt (NS; 0.4% NaCl) or high salt (HS; 4% NaCl) diets. Systemic BP was measured by tail-cuff plethysmography. At the end of treatment period, kidneys were harvested after sacrificing the mice with euthanasia. Immuno-histochemical analysis of TNFR1 and TNFR2 proteins in renal tissues was performed by measuring the staining area and the intensity of receptors’ immunoreactivities using NIS-Elements software. The results were expressed in percent area of positive staining and the relative intensity.

Results:

HS intake alone did not alter mean BP (HS; 77 ± 1 vs. NS; 76 ± 3 vs. mmHg; tail-cuff plethysmography) but AngII induced increases in BP were augmented in HS group (104 ± 2 vs. 95 ± 2 mmHg; P < 0.05). The area of TNFR1 staining was higher in HS than NS group (6.0 ± 0.9% vs. 3.2 ± 0.7%; P < 0.05) but it was lower in AngII + HS than in AngII + NS group (5.0 ± 0.7% vs. 6.3 ± 0.7%; P = 0.068). TNFR2 immunoreactivity was minimal in NS and HS groups but it was high in AngII + NS and even higher in AngII + HS group.

Conclusions:

These data suggest that the HS induced increased TNFR1 activity that facilitates enhanced sodium excretion is compromised in elevated AngII condition leading to salt retention and augmented hypertension.

Dewan S. A. Majid ... L. Gabriel Navar

Published: April 26, 2022 Explor Med. 2022;3:205–218
DOI: https://doi.org/10.37349/emed.2022.00086

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Aim:

Chronic high salt (HS) intake causes minimal changes in blood pressure (BP) but it induces augmented hypertensive response to angiotensin II (AngII) administration in rodents. The mechanism of this augmentation is not clearly understood. As tumor necrosis factor-alpha (TNF-α) induces natriuresis by activating TNF-α receptor type 1 (TNFR1) but not type 2 (TNFR2), we hypothesize that TNFR1 activity is reduced when HS is given in combination of AngII that leads to enhanced sodium retention and thus, causing augmented hypertension. The aim of this study is to examine the responses to chronic HS intake and AngII administration on the renal tissue protein expressions of TNFR1 and TNFR2 in mice.

Methods:

Different groups of mice (n = 6–7 in each group) chronically treated with or without AngII (25 ng/min; implanted minipump) for 4 weeks which were fed either normal salt (NS; 0.4% NaCl) or high salt (HS; 4% NaCl) diets. Systemic BP was measured by tail-cuff plethysmography. At the end of treatment period, kidneys were harvested after sacrificing the mice with euthanasia. Immuno-histochemical analysis of TNFR1 and TNFR2 proteins in renal tissues was performed by measuring the staining area and the intensity of receptors’ immunoreactivities using NIS-Elements software. The results were expressed in percent area of positive staining and the relative intensity.

Results:

HS intake alone did not alter mean BP (HS; 77 ± 1 vs. NS; 76 ± 3 vs. mmHg; tail-cuff plethysmography) but AngII induced increases in BP were augmented in HS group (104 ± 2 vs. 95 ± 2 mmHg; P < 0.05). The area of TNFR1 staining was higher in HS than NS group (6.0 ± 0.9% vs. 3.2 ± 0.7%; P < 0.05) but it was lower in AngII + HS than in AngII + NS group (5.0 ± 0.7% vs. 6.3 ± 0.7%; P = 0.068). TNFR2 immunoreactivity was minimal in NS and HS groups but it was high in AngII + NS and even higher in AngII + HS group.

Conclusions:

These data suggest that the HS induced increased TNFR1 activity that facilitates enhanced sodium excretion is compromised in elevated AngII condition leading to salt retention and augmented hypertension.

Open Access

Original Article

Development of systolic dysfunction unrelated to myocardial infarction in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study
Aim: While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion. [...] Read more.

Aim:

While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion.

Methods:

We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF < 50%.

Results:

During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P < 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P < 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P < 0.0001).

Conclusions:

In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).

Marcello Chinali ... Richard B. Devereux

Published: April 02, 2022 Explor Med. 2022;3:160–172
DOI: https://doi.org/10.37349/emed.2022.00082

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Aim:

While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion.

Methods:

We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF < 50%.

Results:

During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P < 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P < 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P < 0.0001).

Conclusions:

In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).

Open Access

Original Article

Incident left bundle branch block predicts cardiovascular events and death in hypertensive patients with left ventricular hypertrophy. The LIFE Study
Aim: Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy ( [...] Read more.

Aim:

Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH.

Methods:

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up.

Results:

Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P < 0.05), older age, higher Cornell voltage (both P < 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 0.001).

Conclusions:

These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).

Casper N. Bang ... Peter M. Okin

Published: March 29, 2022 Explor Med. 2022;3:149–159
DOI: https://doi.org/10.37349/emed.2022.00081

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Aim:

Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH.

Methods:

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up.

Results:

Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P < 0.05), older age, higher Cornell voltage (both P < 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 0.001).

Conclusions:

These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).

Open Access

Original Article

Incident atrial fibrillation and heart failure in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study
Aim: The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving [...] Read more.

Aim:

The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving antihypertensive treatment in a prospective trial.

Methods:

Patients who had a history of AF or HF were not included, and the participants had sinus rhythm when they were randomly allocated to blinded study medication. Endpoints were adjudicated.

Results:

Incident AF occurred in 679 patients (7.8%) and HF in 246 patients (2.8%) during 4.7 ± 1.1 years mean follow-up. Incident AF was associated with a > 4-fold increased risk of developing subsequent HF [hazards ratios (HRs) = 4.7; 95% confidence intervals (CIs), 3.1–7.0; P < 0.001] in multivariable Cox analyses adjusting for age, sex, race, randomized treatment, standard cardiovascular risk factors and incident myocardial infarction. The development of HF as a time-dependent variable was associated with a multivariable-adjusted 3-fold increase of the primary study endpoint (HRs = 3.11; 95% CIs, 1.52–6.39; P < 0.001) which was a composite of myocardial infarction, stroke or cardiovascular death. Incident HF was associated with a > 3-fold increased risk of developing subsequent AF (HRs = 3.3; 95% CIs, 2.3–4.9; P < 0.001). This development of AF was associated with a > 2-fold increase of the composite primary study endpoint in multivariable Cox analysis (HRs = 2.26; 95% CIs, 1.09–4.67; P = 0.028).

Conclusions:

Incident atrial fibrillation and heart failure are associated with increased risk of the other in treated hypertensive patients with left ventricular hypertrophy. Such high-risk hypertensive patients who subsequently develop both atrial fibrillation and heart failure have particular high risk of composite myocardial infarction, stroke or cardiovascular death (ClinicalTrials.gov identifier: NCT00338260).

Casper N. Bang ... Peter M. Okin

Published: March 23, 2022 Explor Med. 2022;3:139–148
DOI: https://doi.org/10.37349/emed.2022.00080

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Aim:

The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving antihypertensive treatment in a prospective trial.

Methods:

Patients who had a history of AF or HF were not included, and the participants had sinus rhythm when they were randomly allocated to blinded study medication. Endpoints were adjudicated.

Results:

Incident AF occurred in 679 patients (7.8%) and HF in 246 patients (2.8%) during 4.7 ± 1.1 years mean follow-up. Incident AF was associated with a > 4-fold increased risk of developing subsequent HF [hazards ratios (HRs) = 4.7; 95% confidence intervals (CIs), 3.1–7.0; P < 0.001] in multivariable Cox analyses adjusting for age, sex, race, randomized treatment, standard cardiovascular risk factors and incident myocardial infarction. The development of HF as a time-dependent variable was associated with a multivariable-adjusted 3-fold increase of the primary study endpoint (HRs = 3.11; 95% CIs, 1.52–6.39; P < 0.001) which was a composite of myocardial infarction, stroke or cardiovascular death. Incident HF was associated with a > 3-fold increased risk of developing subsequent AF (HRs = 3.3; 95% CIs, 2.3–4.9; P < 0.001). This development of AF was associated with a > 2-fold increase of the composite primary study endpoint in multivariable Cox analysis (HRs = 2.26; 95% CIs, 1.09–4.67; P = 0.028).

Conclusions:

Incident atrial fibrillation and heart failure are associated with increased risk of the other in treated hypertensive patients with left ventricular hypertrophy. Such high-risk hypertensive patients who subsequently develop both atrial fibrillation and heart failure have particular high risk of composite myocardial infarction, stroke or cardiovascular death (ClinicalTrials.gov identifier: NCT00338260).

Open Access

Original Article

Time-varying serum uric acid predicts new-onset atrial fibrillation in treated hypertensive patients. The LIFE Study
Aim: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based t [...] Read more.

Aim:

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based treatment. Because losartan reduces serum uric acid (SUA) levels, the aim of the present study was to investigate relations of SUA with new-onset AF in the study.

Methods:

Hypertensive patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) and no prior AF (n = 8,243) were treated for 5.0 ± 0.4 years with losartan- or atenolol-based therapy. Associations of SUA with new-onset AF documented by Minnesota coding were assessed by Cox models using SUA and systolic blood pressure as time-varying covariates to take into account changes of SUA related to losartan or diuretic treatment, changes in renal function, and aging.

Results:

Time-varying SUA was associated with new AF defined by Minnesota code [hazard ratio (HR) = 1.19 per 16.8 μmol/L (1 mg/dL), (95% confidence intervals (CIs), 1.12–1.26), P < 0.0001], independent of losartan treatment [HR = 0.75 (95% CIs, 0.61–0.93), P = 0.007], older age [HR = 1.95 per 7.0 years (95% CIs, 1.73–2.20), P < 0.0001], male sex [HR = 1.46 (95% CIs, 1.09–1.94), P = 0.010] and higher Cornell voltage-duration product [HR = 1.10 per 1,023 ms·mm (95% CIs, 1.01–1.21), P = 0.034]. Similar results were obtained in Cox models with SUA levels partitioned according to baseline quartiles and in which AF was defined by physician reports or by both Minnesota coding and physician reports.

Conclusions:

In-treatment SUA is a strong predictor for new-onset AF in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and ECG-LVH. Further research is needed to clarify how uric acid may provoke AF (ClinicalTrials.gov identifier: NCT00338260).

Eran S. Zacks ... Richard B. Devereux

Published: March 17, 2022 Explor Med. 2022;3:128–138
DOI: https://doi.org/10.37349/emed.2022.00079

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Aim:

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based treatment. Because losartan reduces serum uric acid (SUA) levels, the aim of the present study was to investigate relations of SUA with new-onset AF in the study.

Methods:

Hypertensive patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) and no prior AF (n = 8,243) were treated for 5.0 ± 0.4 years with losartan- or atenolol-based therapy. Associations of SUA with new-onset AF documented by Minnesota coding were assessed by Cox models using SUA and systolic blood pressure as time-varying covariates to take into account changes of SUA related to losartan or diuretic treatment, changes in renal function, and aging.

Results:

Time-varying SUA was associated with new AF defined by Minnesota code [hazard ratio (HR) = 1.19 per 16.8 μmol/L (1 mg/dL), (95% confidence intervals (CIs), 1.12–1.26), P < 0.0001], independent of losartan treatment [HR = 0.75 (95% CIs, 0.61–0.93), P = 0.007], older age [HR = 1.95 per 7.0 years (95% CIs, 1.73–2.20), P < 0.0001], male sex [HR = 1.46 (95% CIs, 1.09–1.94), P = 0.010] and higher Cornell voltage-duration product [HR = 1.10 per 1,023 ms·mm (95% CIs, 1.01–1.21), P = 0.034]. Similar results were obtained in Cox models with SUA levels partitioned according to baseline quartiles and in which AF was defined by physician reports or by both Minnesota coding and physician reports.

Conclusions:

In-treatment SUA is a strong predictor for new-onset AF in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and ECG-LVH. Further research is needed to clarify how uric acid may provoke AF (ClinicalTrials.gov identifier: NCT00338260).

Open Access

Original Article

Placental CD4⁺ T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia
Aim: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4⁺ T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously [...] Read more.

Aim:

Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4⁺ T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4⁺ T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4⁺ T cells from normal pregnant (NP) women. However, the role of PE CD4⁺ T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4⁺ T cells stimulate AT1-AA in pregnant nude-athymic rats.

Methods:

CD4⁺ T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4⁺ T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4⁺ T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained.

Results:

MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4⁺ T cells compared to NP nude + NP CD4⁺ T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4⁺ T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4⁺ T cells.

Conclusions:

These results show that placental CD4⁺ T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy.

Kristin E. Reeve ... Babbette LaMarca

Published: February 25, 2022 Explor Med. 2022;3:99–111
DOI: https://doi.org/10.37349/emed.2022.00077

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Aim:

Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4⁺ T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4⁺ T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4⁺ T cells from normal pregnant (NP) women. However, the role of PE CD4⁺ T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4⁺ T cells stimulate AT1-AA in pregnant nude-athymic rats.

Methods:

CD4⁺ T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4⁺ T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4⁺ T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained.

Results:

MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4⁺ T cells compared to NP nude + NP CD4⁺ T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4⁺ T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4⁺ T cells.

Conclusions:

These results show that placental CD4⁺ T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy.

Open Access

Review

Role of angiotensin II in the development of subcellular remodeling in heart failure
The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is ma [...] Read more.

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca²⁺, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca²⁺-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dysfunction during the progression of heart failure.

Sukhwinder K. Bhullar ... Naranjan S. Dhalla

Published: August 31, 2021 Explor Med. 2021;2:352–371
DOI: https://doi.org/10.37349/emed.2021.00054

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The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca²⁺, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca²⁺-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dysfunction during the progression of heart failure.

Open Access

Review

Angiotensin-(1-7) and Mas receptor in the brain
The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher [...] Read more.

The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.

Natalia L. Rukavina Mikusic ... Mariela M. Gironacci

Published: June 30, 2021 Explor Med. 2021;2:268–293
DOI: https://doi.org/10.37349/emed.2021.00046

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The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.

Open Access

Review

Angiotensin peptides in the regulation of adrenal cortical function
The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II r [...] Read more.

The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.

Gian Paolo Rossi ... Teresa Maria Seccia

Published: June 30, 2021 Explor Med. 2021;2:294–304
DOI: https://doi.org/10.37349/emed.2021.00047

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The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.

Open Access

Original Article

Angiotensin-(3-4) modulates the overweight- and undernutrition-induced ACE2 downregulation in renal proximal tubule cells: implications for COVID-19?
Aim: The renal lesions–including severe acute kidney injury–are severe outcomes in severe acute respiratory syndrome coronavirus 2 infections. There are no reports regarding the influence of the nutritional status on the sever [...] Read more.

Aim:
The renal lesions–including severe acute kidney injury–are severe outcomes in severe acute respiratory syndrome coronavirus 2 infections. There are no reports regarding the influence of the nutritional status on the severity and progress of these lesions. Ageing is also an important risk factor.

Methods:
In the present study we compared the influence of overweight and undernutrition on the levels of renal angiotensin converting enzymes 1 and 2 (ACE and ACE2), which were evaluated by Western blotting. Since the renin-angiotensin-aldosterone system (RAAS) has been implicated in the progress of kidney failure during coronavirus disease 2019, the influence of Angiotensin-(3-4) [Ang-(3-4)] was investigated. Ang-(3-4) is the shortest angiotensin-derived peptide, which is considered the physiological antagonist of several Ang II effects.

Results:
Both overweight and undernutrition downregulate the levels of ACE2 without influence on the levels of ACE in proximal tubules from kidney rats. Administration of Ang-(3-4) upregulates ACE2 to levels above the control in overweight but not in undernourished rats.

Conclusions:
Chronic undernourishment and overnourishment conditions play a central role in the renal ACE/ACE2 balance, and that the role of RAAS is also different in overweight and undernutrition.

Rafael Luzes ... Adalberto Vieyra

Published: April 30, 2021 Explor Med. 2021;2:135–145
DOI: https://doi.org/10.37349/emed.2021.00038

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Aim:
The renal lesions–including severe acute kidney injury–are severe outcomes in severe acute respiratory syndrome coronavirus 2 infections. There are no reports regarding the influence of the nutritional status on the severity and progress of these lesions. Ageing is also an important risk factor.

Methods:
In the present study we compared the influence of overweight and undernutrition on the levels of renal angiotensin converting enzymes 1 and 2 (ACE and ACE2), which were evaluated by Western blotting. Since the renin-angiotensin-aldosterone system (RAAS) has been implicated in the progress of kidney failure during coronavirus disease 2019, the influence of Angiotensin-(3-4) [Ang-(3-4)] was investigated. Ang-(3-4) is the shortest angiotensin-derived peptide, which is considered the physiological antagonist of several Ang II effects.

Results:
Both overweight and undernutrition downregulate the levels of ACE2 without influence on the levels of ACE in proximal tubules from kidney rats. Administration of Ang-(3-4) upregulates ACE2 to levels above the control in overweight but not in undernourished rats.

Conclusions:
Chronic undernourishment and overnourishment conditions play a central role in the renal ACE/ACE2 balance, and that the role of RAAS is also different in overweight and undernutrition.

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