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BACKGROUND: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS: Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P

Background: Diffuse large B-cell lymphoma (DLBCL) is globally recognized as the most prevalent and aggressive subtype of non-Hodgkin lymphoma. While conventional treatments are effective initially, the disease can become resistant or relapse over time. This study aimed to examine the differentially expressed genes at the transcriptome level and molecular pathways in DLBCL patients. Methods: This investigation utilized RNA sequencing analysis to compare differentially expressed gene samples from five diffuse large B-cell lymphoma patients with two healthy volunteers. These participants were admitted to UKM Medical Center, Kuala Lumpur between 2019 and 2020. The differentially expressed genes were identified using the DESeq2 R package (version 1.10.1) using a negative binomial distribution model. The obtained P values were corrected with the Benjamin and Hochberg method and identified using a False Discovery Rate threshold of <0.05, with log2 fold change (FC) of ≥2 or ≤-2. Results: Results showed 73 differentially expressed genes between the two groups, among which 70 genes were downregulated, and three genes were upregulated. The differentially expressed genes analyzed with the Reactome pathway were significantly associated with the downregulation of antimicrobial humoral response (P<0.001), neutrophil degranulation (P<0.001), chemokine receptors bind chemokines (P=0.028), defensins (P=0.028) and metabolism of angiotensinogen (P=0.040). Conclusion: These findings suggest that the identified pathways may contribute to cancer progression and weaken the immune response in diffuse large B-cell lymphoma patients. This study offers fresh insights into previously undiscovered downstream targets and pathways modulated by diffuse large B-cell lymphoma. [ABSTRACT FROM AUTHOR]

The study was designed to assess the association of ACE I/D polymorphism with the severity and prognosis of COVID-19 in the Iranian population. Hence, 186 adult patients were categorized into three clinical groups based on the severity of COVID-19: 1) Outpatients or mildly symptomatic patients as control (n = 71); 2) Hospitalized patients or severe symptomatic cases (n = 53); 3) Inpatients led to ICU/death or critically ill patients needed mechanical ventilation (n = 62). The possible association of ACE I/D polymorphism with the risk of comorbidities and serum level of C-reactive protein was evaluated in two severe cases. The results showed that the frequency of D and I alleles are 69.35% and 30.65%, respectively, in the total population. The analysis of allelic frequencies via Fisher's exact test confirmed significantly higher frequency of D allele in both severe groups than that in the mild one, 78.31% in Hospitalized patients (OR = 2.56; 95% CI 1.46 to 4.46; p-value = 0.0011) and 74.19% in Inpatients led to ICU/death (OR = 2.04; 95% CI = 1.22 to 3.43; p-value = 0.0094) compared to 58.45% in Outpatients. The results of genotype proportions displayed an association between COVID-19 severity and DD genotype. Overall, our findings in Iranian patients supported the undeniable role of the DD genotype in the intensity of the disease, comparable to other populations. Furthermore, there is no definite evidence regarding the protective effect of the I allele in our inquiry. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) is known to play an important role in regulating renal hemodynamics. We sought to quantify this effect in an in vivo rat model with high‐resolution renal arterial (RA) impedance. This study examines the effects of ANG II and its type 1 receptor blocker telmisartan (TELM) on RA impedance. In baroreflex-deactivated rats, we measured RA pressure (Pr) and blood flow (Fr) during random ventricular pacing to induce pressure fluctuation at three different mean Pr (60, 80, and 100 mmHg). We then estimated RA impedance as the transfer function from Fr to Pr. The RA impedance was found to align with a three‐element Windkessel model consisting of proximal (Rp) and distal (Rd) resistance and compliance (C). Our study showed Rd reflected the composite characteristics of afferent and efferent arterioles. Rd increased with increasing Pr under the baseline condition with a slope of 1.03 ± 0.21 (× 10−1) min·mL−1. ANG II significantly increased the slope by 0.72 ± 0.29 (× 10−1) min·mL−1 (P < 0.05) without affecting the intercept. TELM significantly reduced the intercept by 34.49 ± 4.86 (× 10−1) mmHg·min·mL−1 (P < 0.001) from the baseline value of 37.93 ± 13.36 (× 10−1) mmHg·min·mL−1, whereas it did not affect the slope. In contrast, Rp was less sensitive than Rd to ANG II or TELM, suggesting Rp may represent the characteristics of elastic large arteries. Our findings provide valuable insights into the influence of ANG II on the dynamics of the renal vasculature. NEW & NOTEWORTHY: This present method of quantifying high-resolution renal arterial impedance could contribute to elucidating the characteristics of renal vasculature influenced by physiological mechanisms, renal diseases, or pharmacological effects. The present findings help construct a lumped-parameter renal hemodynamic model that reflects the influence of angiotensin II. [ABSTRACT FROM AUTHOR]

Angiotensin II is a recently introduced vasopressor, which has been available since 2017. The novelty and the relatively high cost of angiotensin II currently limit its broader application. It induces vasoconstriction by activating the renin–angiotensin–aldosterone system and is currently the sole vasopressor functioning through this pathway. Beyond vasoconstriction, angiotensin II also affects various other physiological processes. Current evidence supports its use in managing vasoplegic and cardiogenic shock in patients who are unresponsive to catecholamines and vasopressin. However, due to limited data, the optimal timing for initiating therapy with angiotensin II, strategies for combining it with other vasopressors, and strategies for its discontinuation remain unclear. Ongoing and planned studies aim to address some of these uncertainties. This article reviews the physiological and pathophysiological effects of angiotensin II, describes its pharmacology, and provides a narrative review of the current literature. [ABSTRACT FROM AUTHOR]

Summary: The objectives of this study were to analyse the impact of both temperature and different isolates on microbial protease production ability and to examine the hypertensive effect of bioactive peptides (BAPs) that inhibit the angiotensin I‐converting enzyme released by fermentation of non‐fat milk. First, the ability of several Yamadazyma spp. isolates, which were previously isolated and identified from several sources, was screened in terms of the production of proteolytic enzymes at 15 and 25 °C. The effect of temperature on proteolysis activity of selected isolates was considerable, and incubation at 25 °C was favourable for protease production. Besides, combinations of three different isolates showed remarkable proteolytic activity during the incubation periods of 24, 48 and 72 h. The highest angiotensin I‐converting enzyme inhibitory (ACE‐I) activity was detected for the combination Yamadazyma spp. BO10 and B514‐1, with an inhibition of 92.5%. The partial purification of peptides by ultrafiltration (cut‐off 10 kDa) has no crucial impact on ACE‐I activity, and further purification might improve their effectiveness. The implications of fermentation with co‐culture may have symbiotic potential to increase the antihypertensive effect of the product. Therefore, these results suggest that Yamadazyma spp. may be used to produce functional products or bioactive peptides presenting health‐promoting attributes. [ABSTRACT FROM AUTHOR]

Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF. [ABSTRACT FROM AUTHOR]

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan (S/V) is the first commercially available angiotensin and eneprilysin receptor blocker worldwide, first approved by the United States Food and Drug Administration in 2015. It presents a clear superiority to renin-angiotensin-aldosterone inhibition alone in terms of reduction in all-cause mortality and cardiovascular mortality in heart failure patients with reduced ejection fraction following the "PARADIGM-HF" study. Therefore, it remains essential to understand its effects on the heart and off target. This approach is crucial not only to minimize potential adverse effects, but also to take full advantage of the benefits that V/S can offer in the management of heart failure. [ABSTRACT FROM AUTHOR]

We hypothesized and investigated whether prenatal exposure to preeclampsia (PE) would simultaneously affect perinatal cardiovascular features and angiotensin system expressions. This prospective study was composed of mother-neonate dyads with (n = 49) and without maternal preeclampsia (n = 48) in a single tertiary medical center. The neonates exposed to PE had significantly larger relative sizes for the left and right coronary arteries and a higher cord plasma level of aminopeptidase-N, which positively correlated with the maternal diastolic blood pressures and determined the relative sizes of the left and right coronary arteries, whereas the encoding aminopeptidase-N (ANPEP) mRNA level in the PE cord blood leukocytes was significantly decreased, positively correlated with the neonatal systolic blood pressures (SBPs), and negatively correlated with the cord plasma-induced endothelial vascular cell adhesion molecule-1 mRNA levels. The PE cord plasma significantly induced higher endothelial mRNA levels of angiotensin II type 1 receptor (AT1R) and AT4R, whereas in the umbilical arteries, the protein expressions of AT2R and AT4R were significantly decreased in the PE group. The endothelial AT1R mRNA level positively determined the maternal SBPs, and the AT4R mRNA level positively determined the neonatal chamber size and cardiac output. In conclusion, PE may influence perinatal angiotensin system and cardiovascular manifestations of neonates across placentae. Intriguing correlations between these two warrant further mechanistic investigation. [ABSTRACT FROM AUTHOR]

Interleukin‐5 (IL‐5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects of IL‐5 on cardiac remodelling. Mice were infused with angiotensin II (Ang II), and the expression and source of cardiac IL‐5 were analysed. The results showed that cardiac IL‐5 expression was time‐ and dose‐dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, IL‐5‐knockout (IL‐5−/−) mice were used to observe the effects of IL‐5 knockout on Ang II‐induced cardiac remodelling. We found knockout of IL‐5 significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross‐sectional areas and worsened cardiac dysfunction in Ang II‐infused mice. IL‐5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Furthermore, the effects of IL‐5 deletion on cardiac remodelling was detected after the STAT3 pathway was inhibited by S31‐201. The effects of IL‐5 on cardiac remodelling and M2 macrophage differentiation were reversed by S31‐201. Finally, the effects of IL‐5 on macrophage differentiation and macrophage‐related cardiac hypertrophy and fibrosis were analysed in vitro. IL‐5 knockout significantly increased the Ang II‐induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co‐cultured with macrophages, and this effect was reversed by S31‐201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co‐cultured. In conclusions, IL‐5 deficiency promote the differentiation of M2 macrophages by activating the STAT3 pathway, thereby exacerbating cardiac remodelling in Ang II‐infused mice. IL‐5 may be a potential target for the clinical prevention of cardiac remodelling. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF. The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4+ T cells, CD8+ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease. [ABSTRACT FROM AUTHOR]

Objective(s): Corilagin (Cor) is reported as beiing hepatoprotective, anti-inflammatory, antibacterial, and anti-oxidant, while the effect on atrial fibrosis remains unknown. Therefore, we investigated the protective effect of Cor in angiotensin II (Ang II)-induced atrial fibrosis and atrial fibrillation (AF). Materials and Methods: C57BL/6 mice (male, 8-10 weeks, n = 40) were subcutaneously infused either with saline or Ang II (2.0 mg/kg/day) and Cor (30 mg/kg) intraperitoneally injected 2 hr before Ang II infusion for 4 weeks. Mice were grouped into the control group (n=8), Cor group (n=8), Ang II group (n=8), and Ang II + Cor group (n=8). Morphological, histological, and biochemical examinations were performed. In vivo, transesophageal burst pacing was used to generate AF. Results: Cor treatment markedly reduced Ang II-induced AF development in mice. Ang II + Cor therapy potentially decreased the atrial fibrotic area. It significantly decreased the increase in smooth muscle alpha-actin (α-SMA), CTGF, Collagen I, and Collagen III expressions brought on by Ang II treatment. Moreover, Ang II + Cor treatment remarkably decreased the malondialdehyde (MDA) content, whereas superoxide dismutase (SOD) and catalase (CAT) activities were potentially increased (all, P<0.001). In addition, Ang II + Cor significantly reduced Ang II-induced interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) concentrations in atrial tissues. Furthermore, Cor significantly inhibited Ang II-induced p-PI3K, p-Akt, and NF-κB p-p65 protein expression in atrial tissues. Conclusion: Our data speculated that Cor could have a protective effect against Ang II-induced atrial fibrosis and AF via down-regulation of the PI3K-Akt pathway. [ABSTRACT FROM AUTHOR]

As a hybrid weapon, two novel series of pyrazoles, 16a‐f and 17a‐f, targeting both COX‐2 and ACE‐1‐N‐domain, were created and their anti‐inflammatory, anti‐hypertensive, and anti‐fibrotic properties were evaluated. In vitro, 17b and 17f showed COX‐2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF‐κB (IC50 1.87 and 2.03 μM, respectively). 17b (IC50 0.078 μM) and 17 f (IC50 0.094 μM) inhibited ACE‐1 comparable to perindopril (PER) (IC50 0.048 μM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF‐κB‐p65 and P38‐MAPK expression by −0.62, −0.22, −0.53, and −0.24 folds, respectively compared to l‐NAME (−0.34, −0.45 folds decline in NF‐κB‐p65 and P38‐MAPK, respectively). 17b reduced ANG‐II expression which significantly reversed the cardiac histological changes induced by L‐NAME. [ABSTRACT FROM AUTHOR]

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe−/− mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe−/− mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans. [ABSTRACT FROM AUTHOR]

L'hyperkaliémie, fréquente en pratique clinique courante, est un facteur de risque majeur de mortalité. Elle affecte principalement les patients présentant une insuffisance rénale chronique (IRC), un diabète ou recevant un traitement par inhibiteurs du système rénine-angiotensine-aldostérone (iSRAA). La prise en charge thérapeutique a pour objectif non seulement d'éviter les complications de l'hyperkaliémie, mais aussi d'éviter l'arrêt des traitements cardio- et néphroprotecteurs comme les iSRAA. L'emploi du polystyrène sulfonate, largement prescrit, est souvent limité par l'acceptabilité des patients. Des données récentes sont venues mettre en doute son innocuité, notamment sa tolérance digestive. Deux nouvelles molécules échangeuses de potassium ont fait leur apparition, le patiromer et le sulfonate de zirconium. Leur intérêt en pratique clinique ainsi que leur acceptabilité en cas de prescription prolongée, restent à démontrer. L'association d'un diurétique thiazidique ou d'un inhibiteur du cotransporteur sodium-glucose de type 2 (iSGLT2) au traitement par iSRAA dans l'IRC, peut également permettre de mieux contrôler la kaliémie. Il n'existe pas à l'heure actuelle de recommandations pour positionner les différents traitements hypokaliémiants. Le choix de ces traitements doit s'adapter aux pathologies du patient et tenir compte des autres effets attendus de ces molécules. Hyperkalemia is common in everyday clinical practice, and is a major risk factor for mortality. It mainly affects patients with chronic renal failure (CKD), diabetes or receiving treatment with inhibitors of the renin-angiotensin-aldosterone system (iRAAS). Therapeutic management aims not only to avoid the complications of hyperkalemia, but also to avoid discontinuation of cardio- and nephroprotective treatments such as iRAAS. The use of polystyrene sulfonate, widely prescribed, is often limited by patient acceptability. Recent data have cast doubt on its safety, particularly in terms of digestive tolerance. Two new potassium exchange molecules have appeared on the market: patiromer and zirconium sulfonate. Their value in clinical practice, and their acceptability in the event of prolonged prescription, remain to be demonstrated. The combination of a thiazide diuretic or an inhibitor of the sodium-glucose cotransporter type 2 (iSGLT2) with iRAAS therapy in CKD, may also improve control of kalemia. At present, there are no recommendations for the positioning of the various hypokalemic treatments. The choice of these treatments must be adapted to the patient's pathologies and consider the other expected effects of these molecules. [ABSTRACT FROM AUTHOR]

Background: The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1–7 has some promise in this regard. Objective: The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1–7. Methods: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. Results: Angiotensin 1–7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1–7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1–7. Angiotensin 1–7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1–7‐triggered cardiac tolerance to I/R. Furthermore, angiotensin 1–7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1–7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1–7 possesses anti‐inflammatory properties, possibly achieved through NF‐kB activity inhibition. Phosphoinositide 3‐kinase, Akt, and NO synthase are involved in the infarct‐reducing effect of angiotensin 1–7. However, the specific end‐effector of the cardioprotective impact of angiotensin 1–7 remains unknown. Conclusion: The molecular nature of the end‐effector of the infarct‐limiting effect of angiotensin 1–7 has not been elucidated. Perhaps, this end‐effector is the sarcolemmal KATP channel or the mitochondrial KATP channel. [ABSTRACT FROM AUTHOR]

Context: Patients with inflammatory bowel disease (IBD) were found to have the higher intestinal expression of Angiotensin-Converting Enzyme2 (ACE2) that could consequently increase susceptibility to COVID-19 infection. Objective: This study reports the outcomes of COVID-19 infection in a large cohort of IBD patients. We compare levels of serum ACE and IFN-α between COVID19 patients with and without IBD. We performed a cross-sectional retrospective multicenter study. Methods: We enrolled patients with IBD screened for SARS-COV-2 in six medical centres in Iran from June to November 2020. The blood samples were drawn to measure COVID-19 IgM and IgG, and serum levels of sACE2, sACE1, and interferon-α, regardless of suspicious symptoms have done the molecular test. Results: A total of 534 IBD patients were included in the study. Of these, 109 (20.0%) cases had detectable IgG and IgM against SARS-CoV-2. sACE2 levels were higher in IBD patients than controls, whereas ACE1and IFN-α levels were similar among groups. [ABSTRACT FROM AUTHOR]

Salt-sensitive hypertension (SS-HT) is characterized by blood pressure elevation in response to high dietary salt intake and is considered to increase the risk of cardiovascular and renal morbidity. Although the mechanisms responsible for SS-HT are complex, the kidneys are known to play a central role in the development of SS-HT and the salt sensitivity of blood pressure (SSBP). Moreover, several factors influence renal function and SSBP, including the renin-angiotensin-aldosterone system, sympathetic nervous system, obesity, and aging. A phenotypic characteristic of SSBP is aberrant activation of the renin-angiotensin system and sympathetic nervous system in response to excessive salt intake. SSBP is also accompanied by a blunted increase in renal blood flow after salt loading, resulting in sodium retention and SS-HT. Obesity is associated with inappropriate activation of the aldosterone mineralocorticoid receptor pathway and renal sympathetic nervous system in response to excessive salt, and mineralocorticoid receptor antagonists and renal denervation attenuate sodium retention and inhibit salt-induced blood pressure elevation in obese dogs and humans. SSBP increases with age, which has been attributed to impaired renal sodium handling and a decline in renal function, even in the absence of kidney disease. Aging-associated changes in renal hemodynamics are accompanied by significant alterations in renal hormone levels and renal sodium handling, resulting in SS-HT. In this review, we focus mainly on the contribution of renal function to the development of SS-HT. [ABSTRACT FROM AUTHOR]

The enzymatic activity of the aspartic protease, renin, is critical for its function in blood pressure regulation and sodium homeostasis. Incubation of so-called native prorenin at low pH leads to its activation. After binding to transition-state mimicking renin inhibitors at neutral pH, prorenin attains the active conformation, as indicated by immunosorbent assay using monoclonal antibodies specific for epitopes of the prosegment or the renin body. A comparison of immunosorbent assay with enzyme-kinetic assay revealed the intermediary steps of prorenin auto-activation/inactivation. The kinetically identified intermediary steps of activation/inactivation correspond with the published crystal structures of free renin, free prorenin, and renin in complex with inhibitors. Both renin and activated prorenin exist in 2 forms, α and β. The α form is active, and the α/β quantity ratio is 2.5. The kidney produces renin and prorenin, while the ovarium, placenta, and eye produce inactive prorenin. The production of renin by these organs has never been demonstrated. We propose that the so-called native prorenin in extracellular fluid, including the circulation, is derived, at least partly, from short-lived active prorenin. Its potential paracrine function is discussed. [ABSTRACT FROM AUTHOR]

BackgroundThe behavior of the comprehensive circulating renin-angiotensin system (RAS) in dogs with myxomatous mitral valve disease (MMVD) before to the onset of congestive heart failure remains largely unexplored.Hypothesis/objectivesThe classical and alternative RAS activity and aldosterone concentrations will be significantly higher in dogs with American College of Veterinary Internal Medicine (ACVIM) stage B2 MMVD compared to normal dogs and dogs with ACVIM stage B1 MMVD.AnimalsOne-hundred seventeen client-owned dogs (normal = 60; B1 = 31; B2 = 26).MethodsProspective observational study. Angiotensin peptides (AP) and aldosterone concentrations were measured using liquid chromatography and mass spectrometry. Angiotensin converting enzymes 1 and 2 (ACE, ACE2) and renin activity surrogates were calculated from AP concentrations. Equilibrium dialysis (ED) and immediate protease inhibition (PI) methods of AP quantification were compared in 14 healthy dogs.ResultsCore RAS activity and aldosterone concentrations did not differ among the 3 groups. However, the balance between the alternative and classical RAS differed, with dogs with stage B2 MMVD having significantly higher ACE2 activity surrogate (ACE2surr ) when compared to normal dogs (adjusted P = .02; ratio of medians for ACE2surr [B2:normal], 1.89; 95% confidence interval [CI]: 1.4-2.6). The ED and PI methods of AP quantification were highly correlated (AngI, r = .9, P

The three striatins (STRN, STRN3, STRN4) form the core of STRiatin-/nteracting Phosphatase and Kinase (STRIPAK) complexes. These place protein phosphatase 2A (PP2A) in proximity to protein kinases thereby restraining kinase activity and regulating key cellular processes. Our aim was to establish if striatins play a significant role in cardiac remodelling associated with cardiac hypertrophy and heart failure. All striatins were expressed in control human hearts, with up-regulation of STRN and STRN3 in failing hearts. We used mice with global heterozygote gene deletion to assess the roles of STRN and STRN3 in cardiac remodelling induced by angiotensin II (AngII; 7 days). Using echocardiography, we detected no differences in baseline cardiac function or dimensions in STRN+/- or STRN3+/-male mice (8 weeks) compared with wild-type littermates. Heterozygous gene deletion did not affect cardiac function in mice treated with AngII, but the increase in left ventricle mass induced by AngII was inhibited in STRN+/- (but not STRN3+/-) mice. Histological staining indicated that cardiomyocyte hypertrophy was inhibited. To assess the role of STRN in car-diomyocytes, we converted the STRN knockout line for inducible cardiomyocyte-specific gene deletion. There was no effect of cardiomyocyte STRN knockout on cardiac function or dimensions, but the increase in left ventricle mass induced by AngII was inhibited. This resulted from inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. The data indicate that cardiomyocyte striatin is required for early remodelling of the heart by AngII and identify the striatin-based STRIPAK system as a signalling paradigm in the development of pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Introduction: Sleep insufficiency has been linked to an increased risk of high blood pressure and cardiovascular diseases. Emerging studies have demonstrated that impaired baroreflex sensitivity (BRS) is involved in the adverse cardiovascular effects caused by sleep deprivation, however, the underlying mechanisms remain unknown. Therefore, the present study aims to clarify the role of abnormal renin-angiotensin system in the nucleus tractus solitarii (NTS) in impaired BRS induced by sleep deprivation. Methods: Rats were randomly divided into two groups: normal sleep (Ctrl) and chronic sleep deprivation (CSD) group. Rats were sleep deprived by an automated sleep deprivation system. The blood pressure, heart rate, BRS, the number of c-Fos positive cells and the expression of angiotensin (Ang) II subtype I receptors (AT1R) in the NTS of rats were assessed. Results: Compared to Ctrl group, CSD group exhibited a higher blood pressure, heart rate, and reduced BRS. Moreover, the number of c-Fos positive cells and local field potential in the NTS in CSD group were increased compared with the Ctrl group. It was shown that the expression of the AT1R and the content of Ang II and the ratio of Ang II to Ang-(1-7) were increased in the NTS of rats in CSD group compared to Ctrl group. In addition, microinjection of losartan into the NTS significantly improved the impaired BRS caused by sleep deprivation. Discussion: In conclusion, these data suggest that the elevated AT1R expression in the NTS mediates the reduced BRS induced by chronic sleep deprivation. [ABSTRACT FROM AUTHOR]

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Naþ/Hþ exchanger 3 (NHE3) activity along the proximal tubule but higher Naþ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Naþ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and Kþ-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Naþ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Naþ transport. [ABSTRACT FROM AUTHOR]

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD. [ABSTRACT FROM AUTHOR]

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCβ) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles. [ABSTRACT FROM AUTHOR]

This study investigated the link between angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism and unexplained spontaneous abortion. This retrospective analytical case-control was conducted at the Omdurman Maternity Hospital in Sudan. The current study contained 230 individuals, including 119 cases (women who had at least three abortions) of unknown cause and 119 controls (healthy women who had at least two full-term deliveries without spontaneous abortion). Patients and controls were provided five ml of ethylenediaminetetraacetic acid blood and answered questionnaires about their demographics, personal lives, and family histories. ACE I/D polymorphisms were assessed using a conventional polymerase chain reaction approach after total genomic DNA was isolated from blood leukocytes using the GF-1 blood DNA extraction kit. Data was analyzed using the Statistical Package for the Social Sciences version 24. ACE I/D polymorphism is strongly linked to unexplained spontaneous abortion, and women with the I/D and D/D genotypes are more likely to have it than those with the I/I genotype. The current study reveals that ACEI/D polymorphism increases pregnancy problems. Sudanese women may have spontaneous abortions due to the ACE I/D polymorphism. [ABSTRACT FROM AUTHOR]

The early myocardial response of hypertension is an elevation of angiotensin‐II (Ang‐II) concentration, leading to heart failure and cardiac hypertrophy. This hypertrophic event of the heart is mediated by the interaction of Ang type 1 receptors (AT‐R1), thereby modulating NADPH oxidase activity in cardiomyocytes, which alters redox status in cardiomyocytes. Ellagic acid (EA) has anti‐inflammatory and anti‐oxidative capacities. Thus, EA has potential preventive effects on cardiovascular diseases and diabetes. In the last decades, because the protective effect of EA on Ang‐II‐induced hypertrophic responses is unclear, this study aims to investigate the protective effect of EA in cardiomyocytes. H9c2 cells were treated to Ang‐II 1 μM for 24 h to induce cellular damage. We found that EA protected against Ang‐II‐increased cell surface area and pro‐hypertrophic gene expression in H9c2. EA reduced Ang‐II‐caused AT‐R1 upregulation, thereby inhibiting oxidative stress NADPH oxidase activation. EA mitigated Ang‐II‐enhanced p38 and extracellular‐signal‐regulated kinase (ERK) phosphorylation. Moreover, EA treatment under Ang‐II stimulation also reversed NF‐κB activity and iNOS expression. This study shows that EA protects against Ang‐II‐induced myocardial hypertrophy and attenuates oxidative stress through reactive oxygen species‐mediated mitogen‐activated protein kinase signaling pathways in H9c2 cells. Thus, EA may be an effective compound for preventing Ang‐II‐induced myocardial hypertrophy. [ABSTRACT FROM AUTHOR]

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension‐induced heart injury remains unclear. In vivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. In vitro, H9C2 cells were stimulated with Ang II (1 μM) and treated with Baicalin (12.5, 25 and 50 μM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II‐induced cell apoptosis in vivo and in vitro. Baicalin treatment reversed the up‐regulation of Bax, cleaved‐caspase 3, cleaved‐caspase 9, and the down‐regulation of Bcl‐2. Meanwhile, Baicalin treatment alleviated Ang II‐induced increase of autophagosomes, restored autophagic flux, and down‐regulated LC3II, Beclin 1, as well as up‐regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3‐methyladenine treatment alleviated the increase of autophagosomes and the up‐regulation of Beclin 1, LC3II, Bax, cleaved‐caspase 3, cleaved‐caspase 9, down‐regulation of SQSTM1/p62 and Bcl‐2 expression after Ang II treated, which similar to co‐treatment with Baicalin. Baicalin treatment reduced the ratio of p‐AMPK/AMPK, while increased the ratio of p‐mTOR/mTOR. Baicalin alleviated Ang II‐induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway. [ABSTRACT FROM AUTHOR]

Introduction: Angiotensin (1– 7) (Ang-(1-7)) is an emerging component of the renin-angiotensin system (RAS) with effective anti-fibrosis properties and has been shown to interfere with epithelial-mesenchymal transition (EMT) by numerous studies. In recent years, EMT has been proposed as a new therapeutic target for skin fibrotic diseases such as keloids. However, the effect of Ang-(1-7) on EMT in skin is still unclear. Hence, the purpose of this study was to explore the effect of Ang-(1-7) on Transforming growth factor-β 1(TGF-β 1)–induced EMT of human immortalized keratinocytes HaCaT in vitro. Methods: The study involved the use of the human immortalized keratinocyte cell line (HaCaT). The cells were cultured in high-glucose DMEM medium with 10% fetal bovine serum and 1% penicillin-streptomycin. Four groups were created for experimentation: control group (Group C), TGF-β 1-treated group (Group T), Ang-(1-7)-treated group (Group A), and a group treated with both TGF-β 1 and Ang-(1-7) (Group A + T). Various assays were conducted, including a cell proliferation assay using CCK-8 solution, a scratch wound healing assay to evaluate cell migration, and Western blotting to detect protein expressions related to cell characteristics. Additionally, quantitative real-time polymerase chain reaction (PCR) was performed to analyze epithelial-mesenchymal transition (EMT) related gene expression levels. The study aimed to investigate the effects of TGF-β 1 and Ang-(1-7) on HaCaT cells. Results: We found that Ang-(1-7) not only reduced the migration of HaCaT cells induced by TGF-β 1 in vitro but also reduced the expression of α-SMA and vimentin, and restored the protein expression of E-cadherin and claudin-1. Mechanistically, Ang-(1-7) inhibits the phosphorylation levels of Smad2 and Smad3 in the TGF-β 1 canonical pathway, and suppresses the expression of EMT-related transcription factors (EMT-TFs) such as SNAI2, TWIST1, and ZEB1. Discussion: Taken together, our findings suggest that Ang-(1-7) inhibits TGF-β 1–induced EMT in HaCaT cells in vitro by disrupting the TGF-β 1-Smad canonical signaling pathway. These results may be helpful in the treatment of EMT in skin fibrotic diseases such as keloids. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a prevalent health concern associated with various pathological conditions, including hypertensive nephropathy. Mesangial cells are crucial in maintaining glomerular function, yet their involvement in CKD pathogenesis remains poorly understood. Recent evidence indicates that overactivation of Pannexin-1 (Panx1) channels could contribute to the pathogenesis and progression of various diseases. Although Panx1 is expressed in the kidney, its contribution to the dysfunction of renal cells during pathological conditions remains to be elucidated. This study aimed to investigate the impact of Panx1 channels on mesangial cell function in the context of hypertensive nephropathy. Using an Ang II-infused mouse model and primary mesangial cell cultures, we demonstrated that in vivo exposure to Ang II sensitizes cultured mesangial cells to show increased alterations when they are subjected to subsequent in vitro exposure to Ang II. Particularly, mesangial cell cultures treated with Ang II showed elevated activity of Panx1 channels and increased release of ATP. The latter was associated with enhanced basal intracellular Ca2+ ([Ca2+]i) and increased ATP-mediated [Ca2+]i responses. These effects were accompanied by increased lipid peroxidation and reduced cell viability. Crucially, all the adverse impacts evoked by Ang II were prevented by the blockade of Panx1 channels, underscoring their critical role in mediating cellular dysfunction in mesangial cells. By elucidating the mechanisms by which Ang II negatively impacts mesangial cell function, this study provides valuable insights into the pathogenesis of renal damage in hypertensive nephropathy. [ABSTRACT FROM AUTHOR]

Microalbuminuria has been established as a reliable predictive marker for diabetic nephropathy. Angiotensin-converting enzyme inhibitors, as part of antihypertensive treatment, have shown efficacy in reducing microalbuminuria and protecting renal function. This study aimed to analyze microalbuminuria levels and antihypertensive treatment in diabetic patients treated at IESS Jipijapa Hospital during the 2022 period. An observational study with a quantitative cross-sectional retrospective approach was employed, with a study population consisting of patients from the diabetology department. The results revealed a higher incidence of microalbuminuria in men aged 49 to 73 years, with levels exceeding 40 mg/L. However, those receiving antihypertensive treatment showed microalbuminuria levels below 20 mg/L. Pearson's r statistical analysis showed a significant correlation between antihypertensive treatment and microalbuminuria levels, with a p-value < 0.05. In conclusion, a significant impact of antihypertensive treatments on reducing microalbuminuria levels in diabetic patients was observed, highlighting the importance of antihypertensive therapy as an integral part of managing microalbuminuria in this population. [ABSTRACT FROM AUTHOR]

Cardiomyocyte hypertrophy is the adaptive response of the heart to various physiological or pathological stresses. To combat this type of disease, more effective drugs are still needed. Wedelolactone is the main ingredient extracted from the medicinal plant Daylily and have effects such as immunomodulatory, anti-fibrosis, and anti-inflammation. However, the role and mechanism of Wedelolactone in myocardial hypertrophy are still unclear. Here, H9C2 cells were treated with Ang II to construct a cardiomyocyte hypertrophy cell model. We found Wedelolactone suppressed the survival of Ang II-induced cardiomyocytes. Wedelolactone further restrained the progression of Ang II-induced cardiomyocyte hypertrophy. Wedelolactone suppressed the oxidative stress of Ang II-induced cardiomyocytes, and restrained the apoptosis. Mechanically, Wedelolactone restrained the progression of Ang II-induced cardiomyocyte hypertrophy via Nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 pathway (Nrf2/HO-1 pathway). In summary, Wedelolactone attenuates angiotensin II-induced hypertrophy and apoptosis in cardiomyocytes. Wedelolactone attenuates angiotensin II-stimulated hypertrophy and apoptosis in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727) [Display omitted] [ABSTRACT FROM AUTHOR]

Aldosterone through the mineralocorticoid receptor MR has detrimental effects on cardiovascular disease. It reduces the bioavailability of nitric oxide and impairs endothelium-dependent vasodilatation. In resistance arteries, aldosterone impairs the sensitivity of vascular smooth muscle cells to nitric oxide by promoting the local secretion of histamine which activates H2 receptors. The present experiments tested in vivo and ex vivo the hypothesis that systemic H2-receptor antagonism reduces arterial blood pressure and improves vasodilatation in angiotensin II–induced chronic hypertension. Hypertension was induced by intravenous infusion of angiotensin II (60 ng kg−1 min−1) in conscious, unrestrained mice infused concomitantly with the H2-receptor antagonist ranitidine (27.8 µg kg−1 min−1) or vehicle for 24 days. Heart rate and arterial blood pressure were recorded by indwelling arterial catheter. Resistance (mesenteric) and conductance (aortae) arteries were harvested for perfusion myography and isometric tension recordings by wire myography, respectively. Plasma was analyzed for aldosterone concentration. ANGII infusion resulted in elevated arterial blood pressure and while in vivo treatment with ranitidine reduced plasma aldosterone concentration, it did not reduce blood pressure. Ranitidine improved ex vivo endothelial function (acetylcholine 10−9 to 10−6 mol L−1) in mesenteric resistance arteries. This was abolished by ex vivo treatment with aldosterone (10−9 mol L−1, 1 h). In aortic segments, in vivo ranitidine treatment impaired relaxation. Activation of histamine H2 receptors promotes aldosterone secretion, does not affect arterial blood pressure, and protects endothelial function in conduit arteries but promotes endothelial dysfunction in resistance arteries during angiotensin II–mediated hypertension. Aldosterone contributes little to angiotensin II–induced hypertension in mice. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder. [ABSTRACT FROM AUTHOR]

At present, the effect of angiotensin II on the biological behavior of smooth muscle cells of thoracic aortic aneurysm is not clear. In this study, thoracic aortic aneurysm rat model (thoracic aortic aneurysm model group) was prepared by applying calcium chloride to blood vessels, and normal rats were taken as a sham operation group (sham group), with 10 rats in each group. The changes of angiotensin II content in plasma and left ventricular myocardial tissue were detected. Normal rat thoracic aortic smooth muscle cells were extracted and divided into the control group, angiotensin II group (1 µg/ml angiotensin II), and angiotensin II+angiotensin receptor blocker group (1×10-6 mol/l candesartan+1 µg/ml angiotensin II). The cholecystokinin cell counting kit-8, flow cytometry, Transwell chamber, scratch healing, and Western blot experiments were used to detect cell proliferation, apoptosis, invasion, migration, and the expression changes of Janus kinase/signal transducers and activators of transcription pathway-related proteins. The results showed that angiotensin II content in left ventricular myocardium of thoracic aortic aneurysm group was higher than that of Sham group (p<0.01). Compared with the control group, angiotensin II group showed increased cell proliferative activity, number of invaded cells, mobility, and expression levels of Ras-related C3 botulinum toxin substrate 1, phosphorylated-Janus kinase 2, phosphorylated-signal transducers and activators of transcription 1, and phosphorylated-signal transducers and activators of transcription 3 proteins, and decreased apoptosis rate (p<0.05). Compared with the angiotensin II group, the cell proliferative activity, the number of invaded cells, and mobility as well as the expression levels of Ras-related C3 botulinum toxin substrate 1, phosphorylated-Janus kinase 2, phosphorylated-signal transducers and activators of transcription 1, and phosphorylatedsignal transducers and activators of transcription 3 proteins in the angiotensin II+angiotensin receptor blocker group were decreased, and the apoptosis rate was increased (p<0.05). These results indicated that angiotensin II could induce the proliferation, invasion, and migration of thoracic aortic aneurysm smooth muscle cells, and promote apoptosis. [ABSTRACT FROM AUTHOR]

Arsenic is a well‐known environmental toxicant and emerging evidence suggests that arsenic exposure has potential skeletal muscle toxicity; however, the underlying mechanism has not yet been clarified. The aim of this study was to investigate the correlation among adverse effects of subchronic and chronic environmental arsenic exposure on skeletal muscle as well as specific myokines secretion and angiotensin II (AngII)–melatonin (MT) axis in rats. Four‐week‐old rats were exposed to arsenite (iAs) in drinking water at environmental relevant concentration of 10 ppm for 3 or 9 months. Results indicated that the gastrocnemius muscle had atrophied and its mass was decreased in rats exposed to arsenite for 9 months, whereas, they had no significant changes in rats exposed to arsenite for 3 months. The levels of serum‐specific myokine irisin and gastrocnemius muscle insulin‐like growth factor‐1 (IGF‐1) were increased in 3‐month exposure group and decreased in 9‐month exposure group, while serum myostatin (MSTN) was increased significantly in 9‐month exposure group. In addition, serum AngII level increased both in 3‐ and 9‐month exposure groups, while serum MT level increased in 3‐month exposure group and decreased in 9‐month exposure group. Importantly, the ratio of AngII to MT level in serum increased gradually with the prolongation of arsenite exposure. It showed a certain correlation between AngII–MT axis and gastrocnemius muscle mass, gastrocnemius muscle level of IGF‐1 or serum levels of irisin and MSTN. In conclusion, the disruption of AngII–MT axis balance may be a significant factor for skeletal muscle atrophy induced by chronic environmental arsenic exposure. [ABSTRACT FROM AUTHOR]

Angiotensin I-converting enzyme (ACE)-inhibiting peptides were isolated from walnut protein isolate (WPI) using ultrasound-assisted extraction. This study aimed to assess the impact of ultrasonic pretreatment on the physicochemical properties of WPI. The optimal extraction conditions for WPI were determined as a 15-min ultrasonic treatment at 400 W. Subsequently, the hydrolysate exhibiting the highest in vitro ACE-inhibiting activity underwent further processing and separation steps, including ultrafiltration, ion exchange chromatography, liquid chromatography-tandem mass spectrometry, ADMET screening, and molecular docking. As a result of this comprehensive process, two previously unidentified ACE-inhibiting peptides, namely Tyr-Ile-Gln (YIQ) and Ile-Tyr-Gln (IYQ), were identified. In addition, a novel peptide, Ile-Lys-Gln (IKQ), was synthesized, demonstrating superior ACE-inhibiting activity and temperature stability. In silico analysis estimated an in vivo utilization rate of 21.7% for IKQ. These peptides were observed to inhibit ACE through an anti-competitive mechanism, with molecular docking simulations suggesting an interaction mechanism involving hydrogen bonding. Notably, both IYQ and IKQ peptides exhibited no discernible toxicity to HUVECs cells and promoted nitric oxide (NO) generation. These findings underscore the potential of ultrasonicated WPI in the separation of ACE-inhibiting peptides and their utility in the development of novel ACE inhibitors for functional food applications. [ABSTRACT FROM AUTHOR]

RATIONALE & OBJECTIVE: Few studies have investigated racial disparities in acute kidney injury (AKI), in contrast to the extensive literature on racial differences in the risk of kidney failure. We sought to study potential differences in risk in the setting of chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We studied 2,720 self-identified Black or White participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study from July 1, 2013, to December 31, 2017. EXPOSURE: Self-reported race (Black vs White). OUTCOME: Hospitalized AKI (≥50% increase from nadir to peak serum creatinine). ANALYTICAL APPROACH: Cox regression models adjusting for demographics (age and sex), prehospitalization clinical risk factors (diabetes, blood pressure, cardiovascular disease, estimated glomerular filtration rate, proteinuria, receipt of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers), and socioeconomic status (insurance status and education level). In a subset of participants with genotype data, we adjusted for apolipoprotein L1 gene (APOL1) high-risk status and sickle cell trait. RESULTS: Black participants (n = 1,266) were younger but had a higher burden of prehospitalization clinical risk factors. The incidence rate of first AKI hospitalization among Black participants was 6.3 (95% CI, 5.5-7.2) per 100 person-years versus 5.3 (95% CI, 4.6-6.1) per 100 person-years among White participants. In an unadjusted Cox regression model, Black participants were at a modestly increased risk of incident AKI (HR, 1.22 [95% CI, 1.01-1.48]) compared with White participants. However, this risk was attenuated and no longer significant after adjusting for prehospitalization clinical risk factors (adjusted HR, 1.02 [95% CI, 0.83-1.25]). There were only 11 AKI hospitalizations among individuals with high-risk APOL1 risk status and 14 AKI hospitalizations among individuals with sickle cell trait. LIMITATIONS: Participants were limited to research volunteers and potentially not fully representative of all CKD patients. CONCLUSIONS: In this multicenter prospective cohort of CKD patients, racial disparities in AKI incidence were modest and were explained by differences in prehospitalization clinical risk factors.

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2. To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension. [ABSTRACT FROM AUTHOR]

Background/Aims: Sinomenine, a pure alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, and sinomenine hydrochloride (SN) has been successfully used for the therapy of rheumatoid arthritis (RA) and kidney diseases. Autophagy is a cytoprotective mechanism used by podocytes and other cells to alleviate the effects of oxidative stress, and angiotensin II (Ang II) significantly promotes podocyte autophagy. However, excessive autophagy may lead to cell death and podocyte depletion. The present study evaluated the effect of SN in podocytes induced by Ang II. Methods: Podocytes were pretreated with graded concentrations (10-8 M ∼ 10-4 M) of SN and then stimulated with Ang II. The LC3B protein and the p47-phox membrane fraction were measured by Western blot. Autolysosomes were assessed by transmission electron microscopy. FACS was used to quantify the ROS produced by podocytes. The translocation of p47-phox to the membrane was investigated by immunofluorescence. Results: The 10-8 M ∼ 10-4 M of SN alone did not effect ROS generation or podocyte autophagy. The 10-8 M and 10-6 M SN attenuated Ang II-induced autophagy in podocytes. Furthermore, SN decreased the level of ROS generation in Ang II-induced podocytes via inhibition of NOX subunit p47-phox translocation to the membrane. Conclusion: The appropriate concentration of SN attenuated Ang II-induced podocyte autophagy through ROS generation, at least in part, by regulating NOX subunit p47-phox translocation to the membrane. [ABSTRACT FROM AUTHOR]

Angiotensin II increases apical plasma membrane pendrin abundance and function. This study explored the role of the small GTPase Rac1 in the regulation of pendrin by angiotensin II. To do this, we generated intercalated cell (IC) Rac1 knockout mice and observed that IC Rac1 gene ablation reduced the relative abundance of pendrin in the apical region of intercalated cells in angiotensin II-treated mice but not vehicle-treated mice. Similarly, the Rac1 inhibitor EHT 1864 reduced apical pendrin abundance in angiotensin II-treated mice, through a mechanism that does not require aldosterone. This IC angiotensin II-Rac1 signaling cascade modulates pendrin subcellular distribution without significantly changing actin organization. However, NADPH oxidase inhibition with APX 115 reduced apical pendrin abundance in vivo in angiotensin II-treated mice. Moreover, superoxide dismutase mimetics reduced Cl- absorption in angiotensin II-treated cortical collecting ducts perfused in vitro. Since Rac1 is an NADPH subunit, Rac1 may modulate pendrin through NADPH oxidase-mediated reactive oxygen species production. Because pendrin gene ablation blunts the pressor response to angiotensin II, we asked if pendrin blunts the angiotensin II-induced increase in kidney superoxide. Although kidney superoxide was similar in vehicle-treated wild-type and pendrin knockout mice, it was lower in angiotensin II-treated pendrin-null kidneys than in wild-type kidneys. We conclude that angiotensin II acts through Rac1, independently of aldosterone, to increase apical pendrin abundance. Rac1 may stimulate pendrin, at least partly, through NADPH oxidase. This increase in pendrin abundance contributes to the increment in blood pressure and kidney superoxide content seen in angiotensin II-treated mice. NEW & NOTEWORTHY This study defines a new signaling mechanism by which angiotensin II modulates oxidative stress and blood pressure. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) increases proximal tubule superoxide (O2-) production more in rats fed a 20% fructose normal-salt diet compared with rats fed a 20% glucose normal-salt diet. A 20% fructose high-salt diet (FHS) increases systolic blood pressure (SBP), whereas a 20% glucose high-salt diet (GHS) does not. However, it is unclear whether FHS enhances ANG II-induced oxidative stress in proximal tubules and whether this contributes to increases in blood pressure in this model. We hypothesized that FHS augments the ability of ANG II to stimulate O2- production by proximal tubules, and this contributes to fructose-induced salt-sensitive hypertension. We measured SBP in male Sprague-Dawley rats fed FHS and GHS and determined the effects of 3 mM tempol and 50 mg/kg losartan for 7 days. We then measured basal and ANG II-stimulated (3.7 × 10-8 M) O2- production by proximal tubule suspensions and the role of protein kinase C. FHS increased SBP by 27 ± 5 mmHg (n = 6, P < 0.006) but GHS did not. Rats fed FHS + tempol and GHS + tempol showed no significant increases in SBP. ANG II increased O2- production by 11 ± 1 relative light units/µg protein/s in proximal tubules from FHS-fed rats (n = 6, P < 0.05) but not in tubules from rats fed GHS. ANG II did not significantly stimulate O2- production by proximal tubules from rats fed FHS + tempol or FHS + losartan. The protein kinase C inhibitor Gö6976 blunted ANG II-stimulated O2- production. In conclusion, FHS enhances the sensitivity of proximal tubule O2- production to ANG II, and this contributes to fructose-induced salt-sensitive hypertension. NEW & NOTEWORTHY A diet containing amounts of fructose consumed by 17 million Americans causes salt-sensitive hypertension. Oxidative stress is an initiating cause of this model of fructose-induced salt-sensitive hypertension increasing blood pressure. This salt-sensitive hypertension is prevented by losartan and thus is angiotensin II (ANG II) dependent. Fructose-induced salt-sensitive hypertension depends on ANG II stimulating oxidative stress in the proximal tubule. A fructose/high-salt diet augments the ability of ANG II to stimulate proximal tubule O2- via protein kinase C. [ABSTRACT FROM AUTHOR]

Background: Angiotensin receptor/neprilysin inhibitor (ARNI) and sodiumglucose cotransporter 2 inhibitor (SGLT2i) have shown a significant protective role against cardiovascular diseases and type 2 diabetes mellitus (T2DM), and there is a growing proportion of patients who are undergoing combined therapy with the two drugs. However, the effect of this combination treatment on renal function has not yet been determined. Methods: This study included 539 patients who were diagnosed with cardiovascular disease combined with T2DM. According to the use of SGLT2i and ARNI, patients were divided into the combination treatment group, SGLT2i group, ARNI group and control group. Primary outcomes were serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) changes in the 6th month and 12th month. Results: In the ARNI group, no significant changes in Scr or eGFR were observed during the follow-up period, while the above indicators showed a trend of deterioration in the other three groups. The univariate analysis results showed that at 6 months of follow-up, the renal function indicators of patients treated with ARNI (either alone or in combination) were better than those treated with SGLT2i alone. After 12 months of follow-up, the Scr results were the same as before, while the difference in eGFR between groups disappeared. After multivariate analysis, in terms of delaying the progression of Scr, the ARNI group was superior to the other groups at the end of follow-up. No significant difference in eGFR was observed between groups during follow-up. Conclusion: In patients with cardiovascular disease and T2DM, combination therapy with ARNI and SGLT2i did not show an advantage over monotherapy in delaying renal insufficiency progression, and renal function seems to be better preserved in patients treated with ARNI alone. [ABSTRACT FROM AUTHOR]

Introduction: Twin gestation is related to a higher risk of hypertensive disorders in pregnancy with possible risk stratification depending on chorionicity. It may be related to differences in plasma renin-angiotensinaldosterone components between monochorionic and dichorionic twin pregnancies. The study aimed to analyze the plasma ANG II and ANG 1-7 concentrations in women with monochorionic and dichorionic twin gestation. Methods: A prospective observational study included 79 women between 32 and 34 weeks of gestation with twin pregnancy (31 with monochorionic gestation and 48 with dichorionic gestation). Angiotensin II and angiotensin 1-7 concentrations were measured in the collected blood samples. Results: No significant differences were observed in angiotensin II concentrations between the dichorionic and monochorionic group with significantly higher levels of angiotensin 1-7 being observed in the dichorionic group. Angiotensin 1-7 level was higher than angiotensin II in 20 women (64.5%) in the monochorionic group and in 42 women (87.5%, p=0.01) in the dichorionic group. Higher plasma concentrations of angiotensin II and lower concentrations of angiotensin 1-7 were found in 5 women with gestational hypertension and in 3 with preeclampsia compared to normotensive women. Discussion: It is the first study investigating angiotensin II and angiotensin 1-7 in twin pregnancies regarding chorionicity. Our results showed that plasma angiotensin 1-7 concentration was related to chorionicity, while plasma angiotensin II level was not. In most women with twin gestation angiotensin 1-7 concentration exceeded the concentration of angiotensin II. A switch in the relation between angiotensin II and angiotensin 1-7 was observed in hypertensive pregnant women. [ABSTRACT FROM AUTHOR]

The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin in the regulation of the coronary blood flow and cardiac contractions. The interactions of angiotensin peptides, AVP, and insulin in the heart and in the brain are also discussed. The intracardiac production and the supply of angiotensin peptides and AVP from the systemic circulation enable their easy access to the coronary vessels and the cardiomyocytes. Coronary vessels and cardiomyocytes are furnished with AT1 receptors, AT2 receptors, Ang (1-7) receptors, vasopressin V1 receptors, and insulin receptor substrates. The presence of some of these molecules in the same cells creates good conditions for their interaction at the signaling level. The broad spectrum of actions allows for the engagement of angiotensin peptides, AVP, and insulin in the regulation of the most vital cardiac processes, including (1) cardiac tissue oxygenation, energy production, and metabolism; (2) the generation of the other cardiovascular compounds, such as nitric oxide, bradykinin (Bk), and endothelin; and (3) the regulation of cardiac work by the autonomic nervous system and the cardiovascular neurons of the brain. Multiple experimental studies and clinical observations show that the interactions of Ang II, Ang(1-7), AVP, and insulin in the heart and in the brain are markedly altered during heart failure, hypertension, obesity, and diabetes mellitus, especially when these diseases coexist. A survey of the literature presented in the review provides evidence for the belief that very individualized treatment, including interactions of angiotensins and vasopressin with insulin, should be applied in patients suffering from both the cardiovascular and metabolic diseases. [ABSTRACT FROM AUTHOR]

The liver is an important organ, and hepatic ischemia–reperfusion (IR) injury is a frequent pathophysiological process that can cause significant morbidity and mortality. Thus, our study aimed to investigate the effect of targeting PI3K/p‐Akt/eNOS (phosphoinositide 3‐kinase/phospho‐protein kinase B/endothelial nitric oxide synthase), Nrf2/HO‐1 (nuclear factor‐erythroid 2‐related factor‐2/heme oxygenase‐1), and NF‐κB/p53 (nuclear factor‐κB/tumor protein 53) signaling pathways by using angiotensin (1–7) [ang‐(1–7)] against hepatic injury induced by IR. Thirty‐two male rats were included in sham group, ang‐(1–7)‐treated group, hepatic IR group, and hepatic IR group treated with ang‐(1–7). The levels of hepatic ang‐(1–7), angiotensin II (Ang II), angiotensin‐converting enzyme 2 (ACE2), HO‐1, malondialdehyde (MDA), PI3K, and p‐Akt were assessed. The expressions of eNOS and B‐cell leukemia/lymphoma‐2 (BCL‐2) in the liver were determined. Histological assessment and immunohistochemical expression of NF‐κB, p53, and Nrf2 were carried out. The levels of reduced glutathione (GSH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) in serum were estimated. Results showed that administration of ang‐(1–7) to hepatic IR rats led to significant amelioration of hepatic damage through a histological evaluation that was associated with significant upregulation of the expressions of PI3K/p‐Akt/eNOS and Nrf2/HO‐1 with downregulation of NF‐κB/p53 signaling pathways. In conclusion, PI3K/p‐Akt/eNOS and Nrf2/HO‐1 signaling pathways are involved in the protective effects of ang‐(1–7) against hepatic damage induced by IR. Therefore, ang‐(1–7) can be used to prevent hepatic IR, which occurs in certain conditions such as liver transplantation, hemorrhagic shock, and severe infection. Significance statement: Our study provides evidence for the involvement of PI3K/p‐Akt/eNOS(phosphoinositide 3‐kinase/phospho‐protein kinase B/endothelial nitric oxide synthase), Nrf2/HO‐1 (nuclear factor‐erythroid 2‐related factor‐2/heme oxygenase‐1), and NF‐κB/p53 (nuclear factor‐κB/p53) signaling pathways in the protective effect of angiotensin‐(1–7) against hepatic ischemia–reperfusion (IR) injury. Thus, targeting these pathways via administration of angiotensin‐(1–7) may play a role in prevention of hepatic IR, which is a common pathophysiological process. [ABSTRACT FROM AUTHOR]