Quercetin prophylaxis protects the kidneys by modulating the renin-angiotensin-aldosterone axis under acute hypobaric hypoxic stress.

The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin prophylaxis. One hour prior to hypobaric hypoxia exposure, male SD rats were orally supplemented with quercetin (50 mg/kg BW) and acetazolamide (50 mg/kg BW) and exposed them to 25,000 ft. (7,620 m) in a simulated environmental chamber for 12 h at 25 ± 2 °C. Different biochemical parameters like renin activity, aldosterone, angiotensin I, ACE 2 were determined in plasma. As a conventional response to low oxygen conditions, oxidative stress parameters (ROS and MDA) were elevated along with suppressed antioxidant system (GPx and catalase) in plasma of rats. Quercetin prophylaxis significantly down regulated the hypoxia induced oxidative stress by reducing plasma ROS & MDA levels with efficient enhancement of antioxidants (GPx and Catalase). Further, hypoxia mediated regulation of renin and ACE 2 proves the outstanding efficacy of quercetin in repudiating altercations in RAAS cascade due to hypobaric hypoxia. Furthermore, differential protein expression of HIF-1α, NFκB, IL-18 and endothelin-1 analyzed by western blotting approves the biochemical outcomes and showed that quercetin significantly aids in the reduction of inflammation under hypoxia. Studies conducted with Surface Plasmon Resonance demonstrated a binding among quercetin and ACE 2 that indicates that this flavonoid might regulate RAAS pathway via ACE 2. Henceforth, the study promotes the prophylaxis of quercetin for the better adaptability under hypobaric hypoxic conditions via modulating the RAAS pathway.

Effects of oral HPΒCD-angiotensin-(1-7) supplementation on recreational mountain bike athletes: a crossover study.

BACKGROUND: Supplementation with Angiotensin-(1-7) [(Ang-1-7)] has received considerable attention due to its possible ergogenic effects on physical performance. The effects of a single dose of Ang-(1-7) on the performance of mountain bike (MTB) athletes during progressive load tests performed until the onset of voluntary fatigue have previously been demonstrated. This study tested the effects of Ang-(1-7) in two different exercise protocols with different metabolic demands: aerobic (time trial) and anaerobic (repeated sprint). METHODS: Twenty one male recreational athletes were given capsules containing an oral formulation of HPßCD-Ang-(1-7) (0.8 mg) and HPßCD-placebo (only HPßCD) over a 7-day interval; a double-blind randomized crossover design was used. Physical performance was examined using two protocols: a 20-km cycling time trial or 4 × 30-s repeated all-out sprints on a leg cycle ergometer. Data were collected before and after physical tests to assess fatigue parameters, and included lactate levels, and muscle activation during the sprint protocol as evaluated by electromyography (EMG); cardiovascular parameters: diastolic and systolic blood pressure and heart rate; and performance parameters, time to complete (time trial), maximum power and mean power (repeated sprint). RESULTS: Supplementation with an oral formulation of HPßCD-Ang-(1-7) reduced basal plasma lactate levels and promoted the maintenance of plasma glucose levels after repeated sprints. Supplementation with HPßCD-Ang-(1-7) also increased baseline plasma nitrite levels and reduced resting diastolic blood pressure in a time trial protocol. HPßCD-Ang-(1-7) had no effect on the time trial or repeat sprint performance, or on the EMG recordings of the vastus lateralis and vastus medialis. CONCLUSIONS: Supplementation with HPßCD-Ang-(1-7) did not improve physical performance in time trial or in repeated sprints; however, it promoted the maintenance of plasma glucose and lactate levels after the sprint protocol and at rest, respectively. In addition, HPßCD-Ang-(1-7) also increased resting plasma nitrite levels and reduced diastolic blood pressure in the time trial protocol. TRIAL REGISTRATION: RBR-2nbmpbc, registered January 6th, 2023. The study was prospectively registered.

[Electroacupuncture preconditioning improves pulmonary function via inhibiting inflammatory response and up-regulating expression of ACE2 and Ang (1-7) in lipopolysaccharide-induced acute lung injury rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) pretreatment on lung functions, inflammatory response, and levels of angiotensin-converting enzyme 2 (ACE2) and angiotensin (1-7) ï¼»Ang (1-7)ï¼½ in rats with sepsis-induced acute lung injury (ALI), so as to explore its mechanisms underlying improvement of ALI. METHODS: Thirty male SD rats were randomly divided into normal, model and EA groups (n=10 in each group). The sepsis-related ALI model was established by intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg). Rats of the EA group received EA (4 Hz/20 Hz, 1-3 mA) stimulation at bilateral ST36 for 30 min, once each day, for 7 days before modeling. The lung functions including forced vital capacity (FVC), forced expiratory volume at 0.1 second (FEV0.1) and FEV0.3 were detected using a respiratory function detector for small animals at 3 h after modeling. The bronchoalveolar lavage fluid (BALF) was collected for assaying the contents of Ang (1-7), tumor necrosis factor-α (TNF-α) and interleukin-1 ß (IL-1ß) using ELISA. The lung wet/dry weight (W/D) ratio, FEV0.1/FVC, and FEV0.3/FVC were calculated. The histopathological changes of lung tissues were displayed by hematoxylin-eosin (H.E.) staining. The expression of ACE2 and mitochondrial assembly receptor (MasR) mRNAs and proteins in the lung tissue was detected by fluorescence quantitative real-time PCR and Western blot, separately. RESULTS: Following modeling, the levels of FVC, FEV0.1, FEV0.3, ratio of FEV0.1/FVC and FEV0.3/FVC, content of Ang (1-7) in the BALF, and the expression levels of ACE2 and MasR mRNAs and proteins in the lung tissue were significantly decreased (P<0.01), while the level of W/D ratio and TNF-α and IL-1ß contents in the BALF significantly increased (P<0.01) in the model group relevant to the normal group. In comparison with the model group, the levels of FVC, FEV0.1, FEV0.3, ratio of FEV0.1/FVC and FEV0.3/FVC, content of Ang (1-7) in the BALF, and expression levels of ACE2 and MasR mRNAs and proteins in the lung tissue were significantly increased (P<0.05, P<0.01), whereas the level of W/D ratio, and TNF-α and IL-1ß contents in the BALF were significantly decreased (P<0.05, P<0.01) in the EA group. H.E. staining showed pulmonary interstitial edema and alveolar septum thickening with severe inflammatory cell infiltration in the model group, which was relatively milder in the EA group. CONCLUSION: EA preconditioning at ST36 can improve pulmonary function in sepsis-related ALI rats, which may be related to its effects in inhibiting inflammatory response and up-regulating ACE2 and MasR expression and Ang (1-7) content in the lung tissue.

Effect of calcifediol supplementation on renin-angiotensin-aldosterone system mediators in dogs with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) leads to low serum concentrations of vitamin D metabolites. Thus, hypovitaminosis D associated with CKD might contribute to disease progression via increased concentration of renin angiotensin aldosterone system (RAAS) mediators. OBJECTIVES: To evaluate whether supplementation with calcifediol affects equilibrium concentrations of selected mediators of the RAAS. We hypothesized that vitamin D supplementation will decrease concentration of circulating RAAS mediators in dogs with CKD. ANIMALS: Six client-owned adult dogs with IRIS Stage 2 and 3 CKD. METHODS: Prospective study. Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2 D), 24,25-dihydroxyvitamin D (24,25[OH]2 D), RAAS mediators (angiotensin I/II/III/IV/1-5/1-7, and aldosterone), and surrogate angiotensin converting enzyme (ACE) activity (calculated by the ratio of angiotensin II to angiotensin I) were evaluated at baseline, after 3 months of calcifediol supplementation, and 2 months after discontinuing administration of supplement. RESULTS: All serum vitamin D metabolite concentrations increased significantly by month 3 (P < .001): 25(OH)D (median 250 ng/mL; range, 204-310), compared to baseline (median 43.2 ng/mL; range, 33.8-58.3 ng/mL); 1,25(OH)2 D (median 66.1 pg/mL; range, 57.3-88.1 pg/mL) compared to baseline (median 35.2 pg/mL; range, 29.3-56.7 pg/mL); 24,25(OH)2 D (median 68.4 ng/mL; range, 22.1-142.0 ng/mL) compared to baseline (median 14.4 ng/mL; range, 9.0-21.3 ng/mL). Calculated ACE activity was significantly lower at month 3 (median 0.5; range, 0.4-1.0) compared to baseline (median 0.7; range, 0.6-1.3; P = .01). There were no significant differences in any of the evaluated RAAS variables at any other time-point. CONCLUSIONS AND CLINICAL IMPORTANCE: Short-term calcifediol supplementation in this small group of CKD dogs appeared to decrease ACE activity.

Role of ACE2-Ang (1-7)-Mas axis in post-COVID-19 complications and its dietary modulation.

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.

Angiotensin (ang) 1-7 inhibits ang II-induced atrial fibrosis through regulating the interaction of proto-oncogene tyrosine-protein kinase Src (c-Src) and Src homology region 2 domain-containing phosphatase-1 (SHP-1)).

To verify whether Ang-(1-7) produces an antagonistic effect on Ang II-mediated atrial remodeling. Ang II-induced HL-1 cell model and a rat model of Ang II-induced atrial remodeling were constructed and intervened with Ang II Ang-(1-7), AngII +Ang-(1-7), Ang II+ c-Src specific inhibitor (SU6656), and Ang II + Ang-(1-7) + SSG (SHP-1/2 specific inhibitor, stibogluconate), respectively. The systolic blood pressure of the rat caudal artery was detected. And trial fibrosis was detected by Picrosirius red staining and Masson's trichrome staining. Expressions of transforming growth factor-ß (TGF-ß), tissue inhibitor of metalloproteinases 1 (TIMP1), Matrix metalloproteinase 2 (MMP-2), connective tissue growth factor (CTGF), galectin-3, α-smooth muscle actin (α-SMA), and collagen I/III were subjected to qPCR and western blot. Furthermore, SHP-1 binding to c-Src was verified by co-immunoprecipitation (Co-IP). Results showed that the expressions of TGF-ß, TIMP1, MMP-2, CTGF, α-SMA, galectin-3, and collagen I were increased markedly in the Ang II intervention group, and the expressions of p-ERK1/2, p-Akt, and p-p38MAPK were also increased dramatically. Ang-(1-7) or SU6656 addition could inhibit the action of Ang II factor, thereby minimizing the expressions of the previously described genes and proteins. Simultaneously, SSG supplement reversed the antagonistic effect of Ang-(1-7) on Ang II, and the latter elevated the blood pressure and induced atrial fibrosis in rats. Ang-(1-7) could reverse the changes related to Ang II-induced atrial fibrosis in rats. In conclusion, Ang-(1-7) antagonized Ang II-induced atrial remodeling by regulating SHP-1 and c-Src, thereby affecting the MAPKs/Akt signaling pathway.

Longdan Xiegan Tang attenuates liver injury and hepatic insulin resistance by regulating the angiotensin-converting enzyme 2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The ancient Chinese herbal formula Longdan Xiegan Tang (LXT, also called Gentiana Longdancao Decoction to Drain the Liver) treats insulin resistance- and inflammation-associated liver injuries in clinical practice. AIM OF THE STUDY: To investigate the molecular mechanisms underlying LXT-elicited improvement of the liver injuries. MATERIALS AND METHODS: Male rats were co-treated with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) for eight weeks. Blood parameters were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. RESULTS: LXT attenuated olanzapine-induced liver injury manifested by hyperactivities of plasma alanine aminotransferase and aspartate aminostransferase, hyperbilirubinemia and hypoalbuminemia. Furthermore, LXT improved hepatic insulin resistance that was indicated by hyperinsulinemia, the increased HOMA-IR index, and hepatic over-phosphorylation of Ser307 in insulin receptor substrate (IRS)1, Ser731 in IRS2, Tyr607 in phosphoinositide 3-kinase p85α and Ser473 in AKT at baseline. Mechanistically, LXT inhibited olanzapine-triggered hepatic over-phosphorylation of both IκB kinase (IKK)α/ß and nuclear factor (NF)κB p65 proteins, and mRNA overexpression of tumor necrosis factor α, interleukin 6, interleukin 1ß and CD68. More importantly, LXT restored the decreases in angiotensin-converting enzyme 2 (ACE2) protein level, and its downstream targets Ang (1-7) content and Mas receptor expression. CONCLUSIONS: The present results demonstrate that LXT attenuates liver injury and hepatic insulin resistance by regulating the ACE2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats. Our findings provide a better understanding of LXT for treatment of insulin resistance- and inflammation-associated liver injuries.

Anti-diarrheal therapeutic potential of diminazene aceturate stimulation of the ACE II/Ang-(1-7)/Mas receptor axis in mice: A trial study.

The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects on the body, especially on the cardiac system and gastrointestinal tract. ACE II is responsible for converting Ang II into the active peptide Ang-(1-7), which in turn binds to a metabotropic receptor, the Mas receptor (MasR). Recent studies have demonstrated that Diminazene Aceturate (DIZE), a trypanosomicide used in animals, activates the ACE II pathway. In this study, we aimed to evaluate the antidiarrheal effects promoted by the administration of DIZE to activate the ACE II/Ang-(1-7)/MasR axis in induced diarrhea mice models. The results show that activation of the ACE II pathway exerts antidiarrheal effects that reduce total diarrheal stools and enteropooling. In addition, it increases Na+/K+-ATPase activity and reduces gastrointestinal transit and thus inhibits contractions of intestinal smooth muscle; decreases transepithelial electrical resistance, epithelial permeability, PGE2-induced diarrhea, and proinflammatory cytokines; and increases anti-inflammatory cytokines. Enzyme-linked immunosorbent assay (ELISA) demonstrated that DIZE, when activating the ACE II/Ang-(1-7)/MasR axis, can still interact with GM1 receptors, which reduces cholera toxin-induced diarrhea. Therefore, activation of the ACE II/Ang-(1-7)/MasR axis can be an important pharmacological target for the treatment of diarrheal diseases.

Ang (1-7)/Mas receptor-axis activation promotes amyloid beta-induced altered mitochondrial bioenergetics in discrete brain regions of Alzheimer's disease-like rats.

Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart from its hemodynamic function in the pathophysiology of Alzheimer's disease (AD). It has been reported that Ang (1-7) ameliorates the cognitive impairment in experimental animals. However, the effect of Ang (1-7)/Mas receptor signaling is yet to be explored in Aß42-induced memory impairment. Aß42 was intracerebroventricularly injected into the male rats on day-1 (D-1) of the experimental schedule of 14 days. All the drugs were administered from D-1 to D-14 in the study design. Aß42 significantly increased the escape latency during Morris water maze (MWM) test on D-10 to13 in the animals. Further, Aß42 significantly decreased the time spent and percentage of total distance travelled in the target quadrant of the rats on D-14 in the MWM test. Aß42 also significantly decreased the spontaneous alteration behavior on D-14 during Y-maze test. Moreover, there was a significant increase in the level of Aß42, decrease in the cholinergic function (in terms of decreased acetylcholine and activity of cholinesterase, and increased activity of acetylcholinesterase), mitochondrial function, integrity and bioenergetics, and apoptosis in all the rat brain regions. Further, Aß42 significantly decreased the level of expression of heme oxygenase-1 in all the rat brain regions. Ang (1-7) attenuated Aß42-induced changes in the behavioral, biochemical and molecular observations in all the selected rat brain regions. However, A779, Mas receptor blocker, significantly abolished the beneficial effects of Ang (1-7) in Aß42-induced cognitive deficit animals. These observations clearly indicate that the Ang (1-7)/Mas receptor activation could be a potential alternative option in the management of AD.

Upregulation of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis by a combination of Yinyanghuo (Herba Epimedii Brevicornus) and Cheqianzi (Semen Plantaginis) improves erectile function in spontaneously hypertensive rats.

OBJECTIVE: To evaluate the effects of a combination of Yinyanghuo (Herba Epimedii Brevicornus) (HEB) and Cheqianzi (Semen Plantaginis) (SP) on erectile dysfunction caused by essential hypertension in spontaneously hypertensive rats (SHRs), and to elucidate the role of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor (ACE2/Ang [1-7]/Mas receptor) axis in this process. METHODS: A total of 24 SHRs were randomly assigned to three groups: SHR-control, low-dose (12.5 g/kg) and high-dose (25 g/kg) HEB+SP (HEBSP). Eight Wistar-Kyoto rats were used as normal controls. HEBSP was administered by oral gavage for 28 d. Erectile function was measured once a week using the Heaton test. After 4 weeks of treatment, the corpus cavernosum was harvested from each rat to measure nitric oxide (NO), nitric oxide synthase (eNOS) and Ang (1-7) levels, as well as ACE2, Mas receptor and neuronal nitric oxide synthase (nNOS) protein expression. RESULTS: After 4 weeks of treatment, HEBSP significantly increased erectile function in the treated group compared with SHR-control group (P < 0.01). Additionally, HEBSP treatment significantly increased cavernosal levels of Ang (1-7), eNOS and NO. Moreover, HEBSP significantly elevated the expression levels of ACE2, Mas receptor and nNOS. These beneficial effects were elevated in the high-dose HEBSP group. CONCLUSION: HEBSP improved erectile function in SHRs by upregulating the ACE2/Ang (1-7)/Mas receptor axis, eNOS and nNOS pathways.

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction.

Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis.

Electroacupuncture (EA) can effectively alleviate anxiety disorders and memory impairments caused by various neurodegenerative diseases; however, the molecular mechanisms underlying its neuroprotective effects are unclear. Previous studies have shown that the renin-angiotensin system (RAS) comprises of two axes with mutual antagonism: the classical angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis and the protective angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/MasR) axis. In this study, we observed that chronic cerebral hypoperfusion (CCH) mediated anxiety-like behavior and memory impairments in spontaneously hypertensive rats (SHR) via upregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and the partial hippocampal protective axis (ACE2/Ang-(1-7)). However, Ang II levels were much higher than those of Ang-(1-7), indicating that the ACE/Ang II/AT1R axis plays a dominant role in the comorbidity of CCH and hypertension. Moreover, candesartan cilexetil (Canc) and perindopril (Peril) were used as positive control drugs. We found that EA, Canc, and Peril attenuated CCH-induced anxiety-like behavior and memory impairments in SHR, potentially via downregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and upregulation of the whole hippocampal protective axis (ACE2/Ang-(1-7)/MasR). These results suggest that EA therapy for CCH with hypertension may be mediated by two hippocampal RAS axes.

Angiotensin-(1-7) reduces doxorubicin-induced cardiac dysfunction in male and female Sprague-Dawley rats through antioxidant mechanisms.

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak (E) (P < 0.05) and early diastole mitral valve annulus peak velocity (e'; P < 0.001) and increased E/e' (P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1-7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 (P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal (P < 0.001) and malondialdehyde (P < 0.001), markers of lipid peroxidation; Ang-(1-7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1-7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase (P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1-7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity.NEW & NOTEWORTHY Ang-(1-7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.

Severe food restriction activates the central renin angiotensin system.

We previously showed that 2 weeks of a severe food restricted (sFR) diet (40% of the caloric intake of the control (CT) diet) up-regulated the circulating renin angiotensin (Ang) system (RAS) in female Fischer rats, most likely as a result of the fall in plasma volume. In this study, we investigated the role of the central RAS in the mean arterial pressure (MAP) and heart rate (HR) dysregulation associated with sFR. Although sFR reduced basal mean MAP and HR, the magnitude of the pressor response to intracerebroventricular (icv) microinjection of Ang-[1-8] was not affected; however, HR was 57 ± 13 bpm lower 26 min after Ang-[1-8] microinjection in the sFR rats and a similar response was observed after losartan was microinjected. The major catabolic pathway of Ang-[1-8] in the hypothalamus was via Ang-[1-7]; however, no differences were detected in the rate of Ang-[1-8] synthesis or degradation between CT and sFR animals. While sFR had no effect on the AT1 R binding in the subfornical organ (SFO), the organum vasculosum laminae terminalis (OVLT) and median preoptic nucleus (MnPO) of the paraventricular anteroventral third ventricle, ligand binding increased 1.4-fold in the paraventricular nucleus (PVN) of the hypothalamus. These findings suggest that sFR stimulates the central RAS by increasing AT1 R expression in the PVN as a compensatory response to the reduction in basal MAP and HR. These findings have implications for people experiencing a period of sFR since an activated central RAS could increase their risk of disorders involving over activation of the RAS including renal and cardiovascular diseases.

Tsantan Sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Tsantan Sumtang, which consists of Choerospondias axillaris (Roxb.) Burtt et Hill, Myristica fragrans Houtt and Santalum album L, is a traditional and common prescription of Tibetan medicine. Tsantan Sumtang originates from Four Tantra with properties of nourishing heart and has been used as a folk medicine for cardiovascular diseases and heart failure in Qinghai, Tibet and Inner Mongolia. Our previous studies found that Tsantan Sumtang showed beneficial effects on right ventricular structure in hypoxia rats, while the underling mechanism remains unclear. AIM OF THE STUDY: To elucidate the underlying mechanisms of Tsantan Sumtang attenuated right ventricular (RV) remodeling and fibrosis of chronic hypoxia-induced pulmonary arterial hypertension (HPAH) rats. MATERIALS AND METHODS: Fifty male Sprague Dawley (SD) rats (170 ± 20 g) were randomly divided into control group, hypoxia group, and hypoxia + Tsantan Sumtang groups (1.0 g·â€¯kg-1·day-1, 1.25 g·â€¯kg-1·day-1, 1.5 g ·kg-1·day-1). Rats in the hypoxia group and hypoxia + Tsantan Sumtang groups were maintained in a hypobaric chamber by adjusting the inner pressure and oxygen content to simulate an altitude of 4500 m for 28 days. The mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), the ratio of RV weight to tibia length (TL) (RV/TL), heart rate (HR) and RV systolic pressure (RVSP) was determined. Histomorphological assay of RV structure was evaluated by hematoxylin and eosin (HE) staining. RV tissue fibrosis was assessed by collagen proportion area (CPA), collagen I, collagen III and hydroxyproline content. CPA was obtained by picro-sirius red staining (PSR). The expression of collagen I and collagen III were detected by immunohistochemistry and western blotting. The hydroxyproline content was detected by alkaline hydrolysis. In addition, the level of angiotensin II (AngII) and angiotensin 1-7 (Ang1-7) in RV tissue was tested by enzyme-linked immune sorbent assay (ELISA). Protein expression of angiotensin-converting enzyme (ACE), AngII, AngII type 1 receptor (AT1R), angiotensin-converting enzyme 2 (ACE2), Mas receptor (Mas) were determined by immunohistochemistry and western blotting. mRNA level of ACE, AT1R, ACE2, Mas were tested by qPCR. The chemical profile of Tsantan Sumtang was revealed by UHPLC-Q-Exactive hybrid quadrupole-orbitrap mass analysis. RESULTS: Our results showed that RVHI, RV/TL and RVSP were significantly increased in HPAH rat. Furthermore, levels of collagen I, collagen III and hydroxyproline were up-regulated in RV tissue under hypoxia. We found that RV hypertrophy and fibrosis were associated with increased expression of ACE, AngII, AT1R as well as decreased expression of ACE2, Ang1-7 and Mas. RV remodeling and fibrosis were attenuated after Tsantan Sumtang administration by up-regulating ACE2 and Mas level as well as down-regulating ACE, AngII and AT1R levels in RV tissue. 35 constituents in Tsantan Sumtang were identified. CONCLUSION: Tsantan Sumtang attenuated RV remodeling and fibrosis in rat exposed to chronic hypoxia. The pharmacological effect of Tsantan Sumtang was based on equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas axis of RV tissue in HPAH rat.

[Effect of Tripterygium Glycosides Tablets on synovial angiogenesis in rats with type â ¡ collagen induced arthritis].

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 µg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.

Ang-(1-7) treatment attenuates lipopolysaccharide-induced early pulmonary fibrosis.

Early pulmonary fibrosis is the leading cause of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, whether the renin-angiotensin system (RAS) can serve as a therapeutic target is unknown. In this study, an animal model of early pulmonary fibrosis was established via the LPS three-hit regimen. Afterwards, the animals were treated with intraperitoneal injections of Ang-(1-7), AVE0991, or A779 once per day for 20 days. The plasma and BALF AngII levels of the animals were increased, while there were no significant changes in Ang-(1-7) levels in lung tissue after LPS treatment. Furthermore, the AT1R protein levels were significantly increased and the Mas levels were significantly decreased on days 14 and 21. Administration of Ang-(1-7) downregulated LPS-induced AT1R mRNA expression, which was upregulated by A779. The expression of Mas mRNA responded in the opposite direction relative to AT1R. Moreover, LPS caused decreased levels of Mas and E-cadherin and increased AT1R, Vimentin, and Src phosphorylation levels. Ang-(1-7) or AVE0991 blocked these effects but was counteracted by A779 treatment. Our findings suggested that AngII and AT1R levels exhibit opposite dynamic trends during LPS-induced early pulmonary fibrosis, as do Ang-(1-7) and Mas. Ang-(1-7) exerts protective effects against early pulmonary fibrosis, mainly by regulating the balance between AngII and AT1R and between Ang-(1-7) and Mas and by inhibiting Src kinase activation.

Sini decoction ameliorates sepsis-induced acute lung injury via regulating ACE2-Ang (1-7)-Mas axis and inhibiting the MAPK signaling pathway.

Sepsis, as life-threatening organ dysfunction caused by a dysregulated host response to infection, is characterized by the extensive release of cytokines and other mediators. Sini decoction (SND), a traditional Chinese prescription medicine, has been used clinically for the treatment of sepsis. But its explicit mechanism of action is still unclear. The present study aims to evaluate the potential protective effects of SND on sepsis-induced acute lung injury (ALI). After SND intervention, the lung tissues of each experimental group were collected. H&E sections were used to observe the pathological changes of lung tissue, and alveolar lavage fluid was collected to detect the infiltration of inflammatory cells. Level of inflammatory factors in lung tissue were analyzed by qRT-PCR. The change of Renin angiotensin system (RAS), as well as downstream MAPK/NF-κB signaling pathways were measured by Western blot. For in vitro experiments, human umbilical vein endothelial cells (HUVECs) were pretreated with lipopolysaccharide (LPS) and treated with SND. Subsequently, the expression levels of RAS and MAPK/NF-κB signaling pathways were measured by Western blot. In vivo, we found that SND significantly attenuated sepsis-induced pathological injury in the lung. SND also inhibited LPS-mediated inflammatory cell infiltration, the expression of pro-apoptotic proteins and the production of IL-6, IL-1ß, TNF-α and MCP-1. In vitro, experiments using a co-culture of HUVECs with SND showed that there was a decrease in pro-apoptotic protein and pro-inflammatory mediator. In this research, we also found that SND protective action could be attributed to the regulation of renin-angiotensin system (RAS). MAPKs and NF-κB pathways. To conclude, our study demonstrated that SND ameliorates sepsis-induced-ALI via regulating ACE2-Ang (1-7)-Mas axis and inhibiting the MAPK signaling pathway.

Effect of Tripterygium Glycosides Tablets on synovial angiogenesis in rats with type Ⅱ collagen induced arthritis / 中国中药杂志

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 μg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.

Effects of Resveratrol on the Renin-Angiotensin System in the Aging Kidney.

The renin-angiotensin system (RAS), especially the angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) axis, plays an important role in the aging process of the kidney, through increased tissue reactive oxygen species production and progressively increased oxidative stress. In contrast, the angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis, which counteracts the effects of Ang II, is protective for end-organ damage. To evaluate the ability of resveratrol (RSV) to modulate the RAS in aging kidneys, eighteen-month-old male C57BL/6 mice were divided into two groups that received either normal mouse chow or chow containing resveratrol, for six months. Renal expressions of RAS components, as well as pro- and antioxidant enzymes, were measured and mouse kidneys were isolated for histopathology. Resveratrol-treated mice demonstrated better renal function and reduced albuminuria, with improved renal histologic findings. Resveratrol suppressed the Ang II/AT1R axis and enhanced the AT2R/Ang 1-7/MasR axis. Additionally, the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, 8-hydroxy-2'-deoxyguanosine, 3-nitrotyrosine, collagen IV, and fibronectin was decreased, while the expression of endothelial nitric oxide synthase and superoxide dismutase 2 was increased by resveratrol treatment. These findings demonstrate that resveratrol exerts protective effects on aging kidneys by reducing oxidative stress, inflammation, and fibrosis, through Ang II suppression and MasR activation.