Mechanisms linking the renin-angiotensin system, obesity, and breast cancer

Obesity is a complex disease and a global epidemic. It is a risk factor for other chronic diseases including breast cancer, especially in women after menopause. Diverse etiologies underlie the relationship between obesity and breast cancer. Adipose tissue is in part responsible for these interactions. In obesity, adipose tissue undergoes several metabolic dysregulations resulting in the secretion of many pro-inflammatory cytokines, growth factors, and hormones which in turn, can promote tumor microenvironment (TME) formation and cancer progression within the breast tissue. Angiotensin II (Ang II) is a well-known hypertensive hormone produced systemically and locally by the renin-angiotensin system (RAS). Activation of this system in obesity is a potential contributor to local and systemic inflammation in breast adipose tissue. Ang II actions are primarily mediated through binding to its two receptors, type 1 (AT1R) and type 2 (AT2R). RAS inhibitors include angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) which are currently prescribed as safe antihypertensive therapies. Recent studies have explored the potential use of ACE-I and ARBs in breast cancer patients as anti-tumor agents. Therefore, it is vital to understand the role of RAS in breast cancer and identify mechanisms of Ang II and RAS inhibitors in the TME and in obesity and breast cancer crosstalk. In this review, we performed a detailed analysis and discussed mechanisms of Ang II-AT1R interactions in breast cancer with emphasis on obesity-associated breast cancer. We further summarized recent in vitro, in vivo and human studies that used ACE-I/ARB interventions to improve breast cancer outcomes.

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Imbalance of the renin–angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target?

Gut ◽

10.1136/gutjnl-2019-318512 ◽

2019 ◽

Vol 69 (5) ◽

pp. 841-851 ◽

Cited By ~ 48

Author(s):

Mayur Garg ◽

Simon G Royce ◽

Chris Tikellis ◽

Claire Shallue ◽

Duygu Batu ◽

...

Keyword(s):

Ace Inhibitors ◽

Intestinal Inflammation ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Dependent Manner ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Disease Outcomes ◽

Collagen Secretion

ObjectiveWe evaluated the influence of the renin–angiotensin system (RAS) on intestinal inflammation and fibrosis.DesignCultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1–7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies.ResultsHuman colonic myofibroblast proliferation was reduced by Ang (1–7) in a dose-dependent manner (p<0.05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p<0.001). Colonic myofibroblast collagen secretion was reduced by Ang (1–7) (p<0.05) and captopril (p<0.001), and was increased by Ang II (p<0.001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson’s trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=−0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation.ConclusionsThe RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.

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Alternative renin-angiotensin system pathways in adipose tissue and their role in the pathogenesis of obesity

Endocrine Regulations ◽

10.1515/enr-2016-0025 ◽

2016 ◽

Vol 50 (4) ◽

pp. 229-240 ◽

Cited By ~ 18

Author(s):

M Slamkova ◽

S Zorad ◽

K Krskova

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Alternative Pathways ◽

Metabolism Regulation ◽

Mas Receptor ◽

Glucose And Lipid Metabolism

AbstractAdipose tissue expresses all the renin-angiotensin system (RAS) components that play an important role in the adipogenesis, lipid and glucose metabolism regulation in an auto/paracrine manner. The classical RAS has been found to be over-activated during the adipose tissue enlargement, thus elevated generation of angiotensin II (Ang II) may contribute to the obesity pathogenesis. The contemporary view on the RAS has become more complex with the discovery of alternative pathways, including angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor, (pro)renin receptor, as well as angiotensin IV(Ang IV)/AT4 receptor. Ang-(1-7) via Mas receptor counteracts with most of the deleterious effects of the Ang II-mediated by AT1 receptor implying its beneficial role in the glucose and lipid metabolism, oxidative stress, inflammation, and insulin resistance. Pro(renin) receptor may play a role (at least partial) in the pathogenesis of the obesity by increasing the local production of Ang II in adipose tissue as well as triggering signal transduction independently of Ang II. In this review, modulation of alternative RAS pathways in adipose tissue during obesity is discussed and the involvement of Ang-(1-7), (pro)renin and AT4 receptors in the regulation of adipose tissue homeostasis and insulin resistance is summarized.

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Comparative expression analysis of the renin–angiotensin system components between white and brown perivascular adipose tissue

Journal of Endocrinology ◽

10.1677/joe-07-0284 ◽

2008 ◽

Vol 197 (1) ◽

pp. 55-64 ◽

Cited By ~ 90

Author(s):

B Gálvez-Prieto ◽

J Bolbrinker ◽

P Stucchi ◽

A I de las Heras ◽

B Merino ◽

...

Keyword(s):

Adipose Tissue ◽

Renin Angiotensin System ◽

Receptor Expression ◽

Mrna Levels ◽

Ang Ii ◽

Perivascular Adipose Tissue ◽

Angiotensin System ◽

Renin Angiotensin ◽

Vascular Bed ◽

Brown Adipose

Recent studies have demonstrated that the rat adipose tissue expresses some of the components necessary for the production of angiotensin II (Ang II) and the receptors mediating its actions. The aim of this work is to characterize the expression of the renin–angiotensin system (RAS) components in perivascular adipose tissue and to assess differences in the expression pattern depending on the vascular bed and type of adipose tissue. We analyzed Ang I and Ang II levels as well as mRNA levels of RAS components by a quantitative RT-PCR method in periaortic (PAT) and mesenteric adipose tissue (MAT) of 3-month-old male Wistar–Kyoto rats. PAT was identified as brown adipose tissue expressing uncoupling protein-1 (UCP-1). It had smaller adipocytes than those from MAT, which was identified as white adipose tissue. All RAS components, except renin, were detected in both PAT and MAT. Levels of expression of angiotensinogen, Ang-converting enzyme (ACE), and ACE2 were similar between PAT and MAT. Renin receptor expression was five times higher, whereas expression of chymase, AT1a, and AT2 receptors were significantly lower in PAT compared with MAT respectively. In addition, three isoforms of the AT1a receptor were found in perivascular adipose tissue. The AT1b receptor was found at very a low expression level. Ang II levels were higher in MAT with no differences between tissues in Ang I. The results show that the RAS is differentially expressed in white and brown perivascular adipose tissues implicating a different role for the system depending on the vascular bed and the type of adipose tissue.

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Periaortic adipose tissue-specific activation of the renin-angiotensin system contributes to atherosclerosis development in uninephrectomized apoE−/− mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00053.2013 ◽

2013 ◽

Vol 305 (5) ◽

pp. H667-H675 ◽

Cited By ~ 20

Author(s):

Hiroyuki Kawahito ◽

Hiroyuki Yamada ◽

Daisuke Irie ◽

Taku Kato ◽

Yoshiki Akakabe ◽

...

Keyword(s):

Adipose Tissue ◽

Mrna Expression ◽

Atherosclerotic Lesion ◽

Renin Angiotensin System ◽

Model Assessment ◽

Ang Ii ◽

Lesion Area ◽

Perivascular Adipose Tissue ◽

Angiotensin System ◽

Renin Angiotensin

Chronic kidney disease (CKD) is an independent risk factor for the development of cardiovascular disease. The perivascular adipose tissue is closely implicated in the development of atherosclerosis; however, the contribution to CKD-associated atherogenesis remains undefined. Eight-week-old apoE-deficient mice were uninephrectomized and fed a high-cholesterol diet starting at 12 wk of age. The atherosclerotic lesion area in the thoracic aorta was comparable in 16-wk-old uninephrectomized (UNX) mice and sham control mice; however, the lesion area was markedly exaggerated in 20-wk-old UNX mice compared with the control (54%, P < 0.05). While the accumulation of monocytes/macrophages and the mRNA expression levels of inflammatory cytokines/chemokines in the thoracic periaortic adipose tissue (PAT) did not differ between the two groups, angiotensinogen (AGT) mRNA expression and the angiotensin II (ANG II) concentration in the PAT were significantly higher in 16-wk-old UNX mice than in the control (1.9- and 1.5-fold increases vs. control, respectively; P < 0.05). ANG II concentrations in both the plasma and epididymal white adipose tissue (WAT) were comparable between the two groups, suggesting that PAT-specific activation of the renin-angiotensin system (RAS) is primarily involved in CKD-associated atherogenesis. The homeostasis model assessment-insulin resistance (HOMA-IR) index and plasma insulin level after glucose loading were significantly elevated in 16-wk-old UNX mice. In vitro stimulation of preadipocytes with insulin exaggerated the AGT mRNA expression along with increased mRNA expression of PPARγ. These findings suggest that PAT-specific RAS activation probably primarily contributes in accelerating atherosclerotic development in UNX mice and could thus represent a therapeutic target for preventing CKD-associated atherogenesis.

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Use of inhibitors of the renin angiotensin system and COVID-19 prognosis: a systematic review and meta-analysis

10.1101/2020.05.19.20106799 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jessica Barochiner ◽

Rocio Martinez

Keyword(s):

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Random Effect ◽

Renin Angiotensin System ◽

Cochrane Library ◽

Composite Outcome ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Inhibitors

Background: controversy has arisen in the scientific community on whether the use of renin angiotensin system (RAS) inhibitors in the context of COVID-19 would be of benefit or harmful. A meta-analysis of eligible studies comparing the occurrence of severe and fatal COVID-19 in infected patients who were under treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. Methods: PubMed, Google Scholar, the Cochrane Library, MedRxiv and BioRxiv were searched for relevant studies. Fixed-effect models or random-effect models were used depending on the heterogeneity between estimates. Results: a total of fifteen studies with 21,614 patients were included. The use of RAS inhibitors was associated with a non-significant 20% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR 0.81 (95%CI: 0.63-1.04), p=0.10, I2=82%. In a subgroup analysis that included hypertensive subjects only, ACEI/ARB were associated with a 27% significant decrease in the risk of the composite outcome (RR 0.73 (95%CI: 0.56-0.96), p=0.02, I2=65%). Conclusion: the results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis, and could even be protective in hypertensive subjects. Patients should continue these drugs during their COVID-19 illness.

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Discontinuation of the renin–angiotensin system inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes

Therapeutic Advances in Hematology ◽

10.1177/2040620720958299 ◽

2021 ◽

Vol 12 ◽

pp. 204062072095829

Author(s):

George Pavlidis ◽

Sotirios G. Papageorgiou ◽

Efthimia Bazani ◽

Anthi Bouchla ◽

Eirini Glezou ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Lower Risk ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Group A ◽

Group B ◽

Ras Inhibitors

Renin–angiotensin system (RAS) blockade by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) has been related to anemia in various situations. We aimed to investigate whether discontinuation of RAS inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes (LR-MDSs). Seventy-four patients with LR-MDS were divided into three groups matched for gender and age. Group A consisted of 20 hypertensive patients who discontinued RAS inhibitors and received alternative medications. Group B consisted of 26 patients who continued to receive ACEi/ARB and Group C included 28 patients (50% hypertensive) never exposed to ACEi/ARB. Half of the patients in each group were under treatment with recombinant human erythropoietin (rHuEPO). Data were collected at baseline and after 3, 6 and 12 months. Group A showed a significant increase in hemoglobin from 10.4 ± 1g/dL at baseline to 12.6 ± 1.2 g/dL after 12 months ( p = 0.035) and in hematocrit (31.4 ± 3% versus 37.9 ± 4%, p = 0.002). Incident anemia decreased from 100% at baseline to 60% at 12 months ( p = 0.043) despite a concomitant dose reduction in rHuEPO by 18% ( p = 0.035). No changes in hemoglobin and hematocrit were observed in both Group B and Group C. In the subset of patients not treated with rHuEPO, improvement of erythropoiesis was found only in Group A, as measured by changes in hemoglobin (11.5 ± 1 g/dL versus 12.4 ± 1.3 g/dL, p = 0.041) and hematocrit (34.5 ± 3% versus 37.1 ± 4%, p = 0.038) after 12 months. In contrast, Group B and Group C decreased hemoglobin and hematocrit after 12 months ( p < 0.05). In conclusion, discontinuation of ACEi/ARB in LR-MDS patients is followed by a significant recovery of erythropoiesis after 12 months.

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Mortality and Pre‐Hospitalization use of Renin‐Angiotensin System Inhibitors in Hypertensive COVID‐19 Patients

Journal of the American Heart Association ◽

10.1161/jaha.120.017736 ◽

2020 ◽

Vol 9 (21) ◽

Cited By ~ 3

Author(s):

Chen Chen ◽

Feng Wang ◽

Peng Chen ◽

Jiangang Jiang ◽

Guanglin Cui ◽

...

Keyword(s):

Protective Effect ◽

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Renin Angiotensin System ◽

Published Data ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Hypertensive Patients ◽

Renin Angiotensin ◽

Ras Inhibitors

Abstract Background There has been significant controversy regarding the effects of pre‐hospitalization use of renin‐angiotensin system (RAS) inhibitors on the prognosis of hypertensive COVID‐19 patients. Methods and Results We retrospectively assessed 2,297 hospitalized COVID‐19 patients at Tongji Hospital in Wuhan, China, from January 10 th to March 30 th , 2020; and identified 1,182 patients with known hypertension on pre‐hospitalization therapy. We compared the baseline characteristics and in‐hospital mortality between hypertensive patients taking RAS inhibitors (N=355) versus non‐RAS inhibitors (N=827). Of the 1,182 hypertensive patients (median age 68 years, 49.1% male), 12/355 (3.4%) patients died in the RAS inhibitors group vs. 95/827 (11.5%) patients in the non‐RAS inhibitors group (p<0.0001). Adjusted hazard ratio for mortality was 0.28 (95% CI 0.15‐0.52, p<0.0001) at 45 days in the RAS inhibitors group compared with non‐RAS inhibitors group. Similar findings were observed when patients taking angiotensin receptor blockers (N=289) or angiotensin converting enzyme inhibitors (N=66) were separately compared with non‐RAS inhibitors group. The RAS inhibitors group compared with non‐RAS inhibitors group had lower levels of C‐reactive protein (median 13.5 vs. 24.4 pg/mL; p=0.007) and interleukin‐6 (median 6.0 vs. 8.5 pg/mL; p=0.026) on admission. The protective effect of RAS inhibitors on mortality was confirmed in a meta‐analysis of published data when our data were added to previous studies (odd ratio 0.44, 95% CI 0.29–0.65, p<0.0001). Conclusions In a large single center retrospective analysis we observed a protective effect of pre‐hospitalization use of RAS inhibitors on mortality in hypertensive COVID‐19 patients; which might be associated with reduced inflammatory response.

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Recommended Management of Hypertensive Patients with Diabetes for Renin-Angiotensin System (RAS) Inhibitors

10.36502/2020/droa.6161 ◽

2020 ◽

Vol 2 (1) ◽

pp. 4-8

Author(s):

Bando H

Keyword(s):

Cardiovascular Disease ◽

Ace Inhibitors ◽

Angiotensin Receptor Blockers ◽

Antihypertensive Agents ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Hypertensive Patients ◽

Renin Angiotensin ◽

Patients With Diabetes ◽

Ras Inhibitors

Currently, major categories of antihypertensive agents include diuretics, beta-blockers, calcium channel blockers (CCBs), renin-angiotensin system (RAS) inhibitors [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)]. Among them, RAS (ACE inhibitors and ARB) would be recommended to be a first-line treatment when providing antihypertensive agents for hypertensive patients with diabetes, cardiovascular disease, and impaired renal function. Randomized controlled trials (RCT) of RAS inhibitors compared with other antihypertensive showed a rather lower relative risk (RR). They are all-cause death (RR – 0.95), cardiovascular death (RR – 0.84), incidence of cardiovascular disease (RR – 0.93), and incidence of renal dysfunction (RR – 0.91).

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