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. 2024 Oct 16;38(12):5918–5929. doi: 10.1002/ptr.8353

α‐Mangostin Attenuates Blood Pressure and Reverses Vascular Remodeling by Balancing ACE/AT1R and ACE2/Ang‐(1–7)/MasR Axes in Ang II‐Infused Hypertensive Mice

Qi‐Qi Xue 1, Chu‐Hao Liu 1, Dong‐Yan Zhang 1, Ming‐Xuan Li 1, Yan Li 1,✉
PMCID: PMC11634819  PMID: 39410864

ABSTRACT

Hyperuricemia is a common comorbidity of hypertension and probably has a causal relationship with hypertension. Alpha‐mangostin (α‐MG) has been reported to have uric acid lowering effect. This study aimed to investigate the dual effects of α‐MG on blood pressure (BP) and uric acid levels in angiotensin II (Ang II)‐infused hypertensive mice. Male C57BL/6 mice were randomized into five groups: control, Ang II infusion (500 ng/kg/min for 2 weeks), Ang II infusion with gavage administration of α‐MG 4.0 and 8.0 mg/kg and benzbromarone (25 mg/kg) respectively. BP, uric acid levels, vascular structure and function, and renin–Ang II system expressions in the aorta were assessed. Treatment with α‐MG reduced BP, improved endothelial relaxation, and reversed aortic wall thickening and collagen deposition in Ang II‐induced hypertensive mice. It also downregulated Ang II receptor 1 (AT1R) and angiotensin converting enzyme (ACE) expression, while upregulating ACE2, Mas receptor (MasR), and angiotensin (1–7) in the aorta. Moreover, α‐MG demonstrated a significant enhancement in uric acid clearance and reduction in serum uric acid levels. Conversely, benzbromarone did not result in a decrease in BP, indicating that the hypotensive effect of α‐MG may not be necessarily dependent on its urate‐lowering properties. α‐MG can attenuate Ang II‐induced hypertension and reverse vascular remodeling, potentially by balancing the ACE/Ang II/AT1R axis and the ACE2/Ang‐(1–7)/MasR axis. Our findings provide insights into α‐MG as a novel anti‐hypertensive drug especially in patients with hyperuricemia.

Keywords: alpha‐mangostin, hypertension, renin–angiotensin system, uric acid

α‐Mangostin (α‐MG) effectively reduced blood pressure, promoted endothelial relaxation, and reversed vascular remodeling in Angiotensin II‐induced hypertensive mice. The mechanism involved balancing the ACE/Ang II/AT1R and ACE2/Ang (1‐7)/MasR axes, along with the upregulation of eNOS. Furthermore, α‐MG enhanced uric acid clearance through downregulation GLUT9, suggesting its potential as a novel antihypertensive agent, especially for patients with hyperuricemia.

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1. Introduction

Hypertension is the biggest single contributor to the global burden of disease and mortality, and the number of adults affected by hypertension is predicted to increase from 25% (nearly 1 billion) to 29% (1.56 billion) from 2000 to 2025 (GBD 2019 Risk Factors Collaborators 2020; Poulter, Prabhakaran, and Caulfield 2015). Hyperuricemia, a metabolic disorder characterized by abnormal purine metabolism or decreased uric acid excretion, is a common comorbidity of hypertension (Borghi et al. 2022; Bundy et al. 2017; Gois and Souza 2017; Williams et al. 2018). Nearly 25%–40% of untreated hypertensive patients suffer from hyperuricemia and a similar prevalence of hypertension was found in patients with hyperuricemia. When the two risk factors combined, there is a notable escalation of cardiovascular risk. (Bellomo 2015) Therefore, it is of great significance to develop novel drugs for hyperuicemic and hypertensive patients.

Alpha‐mangostin (α‐MG, Figure 1) is a xanthone extracted from Garcinia mangostana Linn. with multiple pharmacologic function, including antiproliferative, pro‐apoptotic, anti‐inflammatory, antioxidant, and neuroprotective properties. (Djeujo et al. 2022; Ma et al. 2019; Oka et al. 2023) Previous studies had been focused on its antitumor effects. (Alam et al. 2023) A recent study found that α‐MG could downregulate renal expression of uric acid transporters, and enhanced 3 h excretion of urinary urate by 46% and reduced the serum uric acid (Sua) level by 35%. (Niu et al. 2023) However, little is known about its role in cardiovascular diseases, especially hypertension. The mechanism of hypertension is complex and multifaceted, which has not so far been fully understood. Vascular dysfunction occurs in the progression of hypertension and involves changes in different regulatory proteins and signaling pathways. (Touyz et al. 2018) Numerous molecular pathways are involved in vasomotor function disturbances, such as renin–angiotensin‐system (RAS), oxidative stress‐related signaling pathway, immunity/inflammation pathway, calcium pathway, NO‐NOsGC‐cGMP pathway. (Guzik and Touyz 2017; Nosalski et al. 2017; Pojoga et al. 2014; Wamhoff, Bowles, and Owens 2006) Aberrant RAS activation plays a crucial role in the developmental of hypertension (Hsu et al. 2021).

FIGURE 1.

FIGURE 1

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Treatment of experimental groups. α‐MG, α‐mangostin; Ang II, angiotensin II.

Given the hypouricemic property of α‐MG and the close relationship between hyperuricemia and hypertension, in this study, we intended to explore the dual effects of α‐MG on blood pressure (BP) and Sua levels in angiotensin II (Ang II)‐infused hypertensive mice and its possible mechanisms. The findings of our study may shed light on α‐MG as an anti‐hypertensive drug, particularly in patients with hyperuricemia.

2. Materials and Methods

2.1. Drugs and Reagents

α‐mangostin (HY‐N0328, purity: 99.64%), benzbromarone (HY‐B1135, purity: 99.81%), and N‐nitro‐L‐arginine (L‐NAME, HY‐18729A, purity: 99.70%) were purchased from MCE (China). Ang II was purchased from Sigma‐Aldrich (Cat#A9525, St Louis, USA). GAPDH (Cat#2118s), endothelial nitric oxide synthase (eNOS) (Cat#32027s), phospho‐eNOS (Cat#9570s), anti‐rabbit IgG (Cat#14709s), and anti‐mouse IgG (Cat#14708s) secondary antibodies were purchased from Cell Signaling (MA, USA). The antibody of glucose transporter 9 (GLUT9, Cat#67530), Mas receptor (MasR, Cat#20080‐1‐AP), collagen type I (Collagen I, Cat# 14695‐1‐AP), collagen type III (Collagen III, Cat# 22734‐1‐AP), α‐SMA (Cat# 67735‐1‐Ig), and CNN1 (Cat# 24855‐1‐AP) were obtained from Proteintech (China). Angiotensin converting enzyme (ACE, Cat#ab254222), ACE2 (Cat#ab108252s), and Ang II receptor 1 (AT1R, Cat#ab124734) were purchased from abcam (MA, USA). BCA Protein Assay Kits (Cat #P0010S) were purchased from Beyotime (China). Mouse Ang‐(1–7) Elisa kit was purchased from Elabscience (Cat#M2681, China).

2.2. Animals and Animal Models

The animal and experimental protocols were conducted according to the Guide for the Care and Use of Laboratory Animals and approved by the animal care and use committee of Shanghai Jiao Tong University (China), which conforms to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes. Eight‐week‐old male SPF‐grade C57BL/6 mice were purchased from Shanghai JieSiJie Laboratory Animal Co., Ltd. To avoid the possible confounding effect of estrogen on BP regulation, only male mice were used in the present study. The mice were kept at 25°C ± 1°C and 65% ± 5% humidity and acclimatized under a 12‐h light/dark cycle in the animal house of Ruijin Hospital, Shanghai Jiaotong University School of Medicine. The mice were placed to adapt to the environment for 1 week prior to experimentation. Body weight of the mice was recorded weekly. All animal experiments followed the reduce, reuse, and recycle (3R) principle.

2.3. Ang II Infusion and α‐Mangostin Treatment

To induce hypertension, male C57BL/6 mice (8 weeks) were infused with Ang II (500 ng/kg/min) for 2 weeks through osmotic minipump subcutaneously implanted under isoflurane anesthesia. The model and the dose of Ang II were chosen according to the AHA Scientific Statement. (Lerman et al. 2019) Mice were randomized into four groups: control, Ang II infusion, and Ang II infusion with gavage administration of α‐MG 4.0 and 8.0 mg/kg, respectively. The control and Ang II‐infused mice were gavaged with 0.5% sodium carboxymethylcellulose (CMC‐Na), and other groups were gavaged with α‐mangostin dissolved in 0.5% CMC‐Na. In addition, we established a benzbromarone group to assess the effect of changes in uric acid levels on BP. Benzbromarone was dissolved in 0.5% CMC‐Na and administered at a dose of 25 mg/kg. All mice were administered at a volume of 0.2 mL twice a day at 9:00 and 17:00. The drug was administered post‐injury, serving as a therapeutic intervention for the experimental disease. Treatments were repeated at least in three independent groups of animals in different time periods.

2.4. Tail‐Cuff Manometry

To measure systolic BP (SBP), diastolic BP, mean BP, and heart rate, we applied an animal sphygmomanometer (BP2010A, Softron Co., Ltd., Tokyo, Japan) using the non‐invasive tail‐cuff method. Mice were trained to actively burrow into a pouch and keep immobilization during the measurement and acclimated for 1 week prior to the initial measurement. The training course was repeated two to three times for each mouse. BP was the average of at least five consecutive and stable measurements.

2.5. Isometric Force Measurements in Aortic Ring

After mice were anesthetized with pentobarbital sodium (30 mg/kg), we incised into the chest cavity with scissors to remove thoracic aorta and excised it into the 3 mm aorta ring stripped of fat and connective tissue. The aortic ring was then isometrically mounted in the bath of the Multi‐Wire Myograph System (DMT610M, Aarhus, Denmark) immersed with Krebs' solution continuously aerated with 95% O2, and 5% CO2. KCl was added to achieve the optimal active tension. The vascular reactivity in contractility and relaxation was studied in gradient concentrations of phenylephrine (PE, 10−9 to 10−5 M), acetylcholine (Ach, 10−9 to 10−5 M), and sodium nitroprusside (SNP, 10−9 to 10−5 M). Some segments were incubated with 10−4 M N‐nitro‐L‐arginine (L‐NAME), a nonselective NOS inhibitor, for 30 min before measuring endothelium‐dependent relaxation. The changes in vascular tension were recorded by PowerLab (AD Instruments) and analyzed by LabChart software (AD Instruments).

2.6. Western Blotting

Protein lysates were prepared in RIPA (BCA, Beyotime, Shanghai) containing protease inhibitors. The concentration was determined with a BCA Kit (BCA, Beyotime, Shanghai), and total protein (20 μg/each sample) was loaded and separated with a 10% SDS‐polyacrylamide gel. Then the proteins were transferred onto a PVDF membrane (Millipore, Bedford, MA, USA), and incubated with ACE (1:1000), ACE2 (1:1000), AT1R (1:200), AT2R (1:1000), GAPDH (1:1000), GLUT9 (1:2000), type I collagen (1:1000), MasR (1:1000), CNN1 (1:1000), type III collagen, and α‐SMA (1:1000) overnight at 4°C, respectively. Following incubation with HRP‐conjugated goat anti‐Rabbit IgG (1:5000) and anti‐Mouse IgG (1:5000) for 1 h at room temperature, the membrane was washed and exposed by using the ImmobilonTM Western chemiluminescent HRP substrate (Millipore, Bedford, MA, USA). GAPDH was used as the internal reference. The quantification of western blot images was performed using Image J software.

2.7. H&E Staining

The mice aorta was collected on the 14th day of the experiment and fixed overnight in 4% paraformaldehyde, and each aorta was then embedded in paraffin. All tissues were sliced into 6‐μm‐thick sections that were then stained with hematoxylin and eosin (H&E) for histological examination.

2.8. Picrosirius Red Staining

Vascular remodeling was assessed by staining collagen with picrosirius red. The sections were stained with sirius red‐picric acid staining solution for 30–60 min at room temperature. The image was photographed with light microscope and polarized light microscope. In sirius red staining, the elongated axis of dye molecules was attached parallel to the collagen fiber, resulting in enhanced birefringency and specificity when combined with polarized light detection methods. (Esquibel et al. 2020).

2.9. Realtime‐PCR

Kidneys were collected from the mice on the 14th day of the experiment. The tissues were cryogenically ground. The total RNA (10ug) was extracted using TRIzol and reverse transcribed into cDNA. Real‐time quantitative PCR was performed using the SYBRGreen PCR Master Mix system to detect the relative mRNA levels of uric acid transporters, including Slc2a9, Slc5a12, Slc22a12, Slc13a13, Slc17a1, Slc17a3, Slc22a6, Slc5a8, Abcg2. The primer sequences are shown in Table S1. The amplification conditions were as follows: initial denaturation at 95°C for 30 s, followed by 40 cycles of denaturation (95°C for 5 s), and annealing (60°C for 31 s). The data were analyzed according to the 2−ΔΔCt method (ΔCt = cycle threshold of the target gene‐cycle threshold of the internal control), GAPDH was used as the internal control, and three technical replicates were run for each sample.

2.10. Serum and Urinary Biochemical Analysis

Mice were housed in metabolic cages for 24‐h urine collection. At the end of the experiment, the mice were anaesthetized by intraperitoneal injection of pentobarbital (30 mg/kg). To obtain the serum, the blood was collected and centrifuged at 3600 g for 10 min. Creatinine and uric acid test kits (C011‐2‐1 and C012‐2‐1, Nanjing Jiancheng Bioengineering Institute, Nanjing, China) were used to assess Sua, serum creatinine (Scr), urinary uric acid (Uua), and urinary creatinine (Ucr). Clearance of creatinine (Ccr) was calculated using the formula Ccr = Uv × Ucr/Scr, in which Uv is the 24‐h urinary volume. Similarly, clearance of uric acid (Cua) was calculated as Uv × Uua/Sua. Ccr and Cua were normalized to a body surface area of 0.0071 m2 (Perez‐Ruiz et al. 2002).

Mice blood was collected in tubes. Serum was collected followed by centrifugation for 15 min at 1000×g within 30 min of collection and then stored at −80°C. Serum angiotensin (1–7) levels were determined by using mouse angiotensin 1–7 (Ang1–7) ELISA Kit (Cat#M2681, Elabscience, China).

2.11. Statistical Analysis

Continuous data are expressed as the mean ± SD. One‐ or two‐way analysis of variance followed by Bonferroni post hoc test were used to evaluate differences between multiple groups. Student's t test was used to compare values among two groups. p < 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 7.0 (GraphPad Prism software). The graphical abstract was conducted by Figdraw, ID:YYIRPc8c99.

3. Results

3.1. Increased Sua and Upregulated Urate Transporter (GLUT9/Slc2a9) in Ang II‐Infused Hypertensive Mice

Chronic infusion of Ang II for 2 weeks in mice increased Sua by 61% (p < 0.05, Figure 2A). To further explore the expression of uric acid transporters in the kidney, we quantified the mRNA levels of ni ne major uric acid transporters (Slc2a9, Slc5a12, Slc22a12, Slc13a13, Slc17a1, Slc17a3, Slc22a6, Slc5a8, Abcg2) by RT‐PCR. Ang II infusion significantly increased the mRNA level of Slc2a9 in the kidneys (p < 0.01, Figure 2A). GLUT9, encoded by Slc2a9 gene, was also upregulated in both kidney and the aorta compared with the control group (p < 0.01, Figure 2B,C). These results suggest that Ang II‐infused hypertension could upregulate GLUT9/Slc2a9 expression, which may be responsible for elevated Sua.

FIGURE 2.

FIGURE 2

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Increased serum uric acid and GLUT9/Slc2a9 in Ang II‐infused hypertensive mice. (A) C57BL/6 male mice were infused with Ang II (500 ng/kg/min) for 2 weeks. Serum uric acid levels are measured in the control group and Ang II group (n = 8, the results are expressed as the mean ± SD, *p < 0.05). Then the mRNA expression of Slc2a9 (GLUT9), Slc5a12, Slc22a12, Slc13a13, Slc17a1, Slc17a3, Slc22a6, Slc5a8, and Abcg2 in kidneys were determined using RT‐PCR, and the relative expression levels were calculated with the control group and GAPDH as the reference gene (n = 5, the results are expressed as the mean ± SD; compared with the control group by the Student's t test, ***p < 0.001). (B, C) The protein expression levels of GLUT9 in kidneys and aorta were detected by western blot. GAPDH was used as the internal control (n = 5 per group, the results are expressed as the mean ± SD; compared with the control group by with the Student's t test, ***p < 0.001).

3.2. α‐MG Downregulates the Expression of GLUT9/Slc2a9 and Promotes the Excretion of UA in the Kidney

α‐MG administration at the dose of 4.0 and 8.0 mg/kg twice daily for 2 weeks reversed upregulation of GLUT9 in both the kidney and aorta of Ang II‐infused hypertensive mice (Figure 3A,B), and decreased Sua in hypertensive mice within 2 weeks. To further assess the role of α‐MG in kidneys, serum, and Ucr, serum urea nitrogen were examined. As expected, Scr was significantly higher in the hypertensive group than in the control group, while Ucr showed the opposite trend. α‐MG significantly reduced serum and Ucr levels in hypertensive mice compared with hypertensive group. Besides, derived parameters, Cua and Ccr, were calculated to evaluate the effect of α‐MG on uric acid metabolism. In the hypertensive group, 24‐h Cua and Ccr were significantly decreased compared with control mice, while rescued after treatment with 4.0 and 8.0 mg/kg α‐MG (Figure 3C–I).

FIGURE 3.

FIGURE 3

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α‐mangostin (α‐MG) downregulated the expression of GLUT9/Slc2a9 and promotes the excretion of uric acid. C57BL/6 male mice were divided into control mice, Ang II‐infused mice, Ang II‐infused mice treated with α‐MG (4.0 mg/kg), Ang II‐infused mice treated with α‐MG (8.0 mg/kg). (A, B) The protein expression levels of GLUT9 in kidneys and aorta were detected by western blot (n = 3, the results are expressed as the mean ± SD; *p < 0.05, # p < 0.05, ## p < 0.01 with the one‐way ANOVA). (C–I) Serum uric acid (Sua), serum creatinine (Scr), urinary uric acid (24 h Uua), and urinary creatinine (24 h Ucr) were detected. Clearance of creatinine (Ccr) was calculated from the formula Ccr = Uv × Ucr/Scr, expressed in mL/min. Clearance of uric acid (Cua) was calculated from the formula Cur = Uv × Uur/Sur, expressed in mL/min. Ccr and Cua were normalized for a body surface area of 0.0071 m2 (n = 6–8, the data are expressed as the mean ± SD, *p < 0.05, **p < 0.01, # p < 0.05, ## p < 0.01, ### p < 0.001 with the one‐way ANOVA).

3.3. BP‐Lowering Effect of α‐MG

The baseline SBP of the C57BL/6 mice ranged from 105 to 115 mmHg. Infusion with Ang II markedly increased the SBP to around 150 mmHg on the third day. Treatment with α‐MG (4.0 and 8.0 mg/kg) prevented the elevation of SBP (Figure 4A). Compared with the Ang II group, SBP was lower in the α‐MG treatment group by an average of about 20 mmHg.

FIGURE 4.

FIGURE 4

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α‐mangostin (α‐MG) attenuated Ang II‐induced hypertension in mice. C57BL/6 male mice were divided into control mice, Ang II‐infused mice, Ang II‐infused mice treated with α‐MG (4.0 mg/kg), Ang II‐infused mice treated with α‐MG (8.0 mg/kg), and Ang II‐infused mice treated with benzbromarone. (A) Systolic blood pressure (SBP), (B) diastolic blood pressure (DBP), (C) heart rate (D), weight (n = 10, the data are expressed as the mean ± SD, *p < 0.05, # p < 0.05, ****p < 0.0001, #### p < 0.0001 with the two‐way ANOVA).

To clarify whether the urate‐lowering effect of α‐MG could result in the antihypertensive effect, we simultaneously administered benzbromarone 25 mg/kg twice daily to Ang II‐infused hypertensive mice. However, treatment with benzbromarone failed to reduce BP in Ang II‐infused mice (Figure 4A,B). In addition, no changes in body weight and heart rate were observed in control and experiment mice (Figure 4C,D). These results suggested that the antihypertensive effect of α‐MG is not necessary for its urate‐lowering effect. In mice without Ang II infusion, α‐MG administration at a dose of 8.0 mg/kg twice daily did not result in any statistically significant alterations in SBP, diastolic BP, heart rate, or body weight, similar like the control group (Figure S1).

3.4. Effect of α‐MG on the Balance of RAS Axes

To clarify the underlying antihypertensive mechanisms of α‐MG, we detected the expression of RAS members in mice aorta. Ang II‐infusion overactivated the classical RAS axis, increasing expression of AT1R and ACE, whereas the counteracting arm of it, the non‐classical ACE2/Ang‐(1–7)/MasR axis was suppressed in the aorta. α‐MG inhibited Ang II‐induced ACE and AT1R upregulation, and at the dose of 4.0 and 8.0 mg/kg increased ACE2 expression and therefore elevated serum Ang‐(1–7) (Figure 5A–H). α‐MG administration ameliorated the suppressed MasR expression in Ang II‐infused hypertensive mice, although this was statistically different only at high‐dose group (8.0 mg/kg) (p < 0.01). α‐MG also can reverse the Ang II‐induced upregulation of ACE/ACE2 and AT1R/MasR ratios (Figure 5F,G). These results suggest that α‐MG may play a role in balancing ACE/AT1R and ACE2/Ang‐(1–7)/MasR axes.

FIGURE 5.

FIGURE 5

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Effects of α‐mangostin on RAS in Ang II‐infused hypertensive mice. C57BL/6 male mice were divided into control mice, Ang II‐infused mice, Ang II‐infused mice treated with α‐MG (4.0 mg/kg), Ang II‐infused mice treated with α‐MG (8.0 mg/kg). (A–G) The protein expression levels of ACE, AT1R, ACE2, and MasR in aorta were detected by western blot. GAPDH was used as the internal control (n = 3–6, the results are expressed as the mean ± SD; *p < 0.05, **p < 0.01, # p < 0.05, ## p < 0.01, #### p < 0.0001 with the one‐way ANOVA). (H) Serum Ang‐(1–7) of experimental mice were detected (n = 8, the results are expressed as the mean ± SD; *p < 0.05, # p < 0.05 with the one‐way ANOVA).

3.5. α‐MG Ameliorates Ang II‐Induced Impairment of Endothelium‐Dependent Relaxation in Aorta

Compared with control group, Ang II infusion significantly blunted endothelium‐dependent relaxation in response to Ach in aorta (Figure 6A). Treatment with α‐MG improved endothelial dysfunction and the protective effect was evident in the high‐dose group (8.0 mg/kg). Endothelium‐dependent relaxation in response to Ach was significant and was blocked by the eNOS inhibitor L‐NAME (10−4 M) (Figure 6C). α‐MG also improved vasoconstriction in response to PE (Figure 6B). However, smooth muscle cell‐dependent relaxation of aorta in response to SNP was not comparable between all groups (Figure 6D). We hypothesized alterations in eNOS expression was the potential mechanism by which α‐MG affects endothelium dependent relaxation. We observed that α‐MG reversed the decrease of eNOS expression induced by Ang II in the aorta. Meanwhile, α‐MG did not promote phosphorylation of eNOS at Ser1176 (Figure 6E,F). These results indicate that α‐MG ameliorates Ang II‐induced impairment of nitric oxide (NO)‐mediated relaxation in the thoracic aorta.

FIGURE 6.

FIGURE 6

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α‐mangostin ameliorated Ang II‐induced endothelial dysfunction in aorta. Vascular function was detected with arterial rings of aorta from four experimental groups: control mice, Ang II‐infused mice, Ang II‐infused mice treated with α‐MG (4.0 mg/kg), Ang II‐infused mice treated with α‐MG (8.0 mg/kg) after Ang II infusion for 14 days. (A–D) acetylcholine (Ach)‐induced endothelium‐dependent relaxation, the concentration–response curves of phenylephrine (PE)‐induced constriction, sodium nitroprusside (SNP)‐induced non‐endothelium‐dependent relaxation and cumulative concentration–response curves to ACh of aortas in the presence of L‐NAME (10−4 M) are shown (n = 5–7, the data are expressed as the mean ± SD, **p < 0.01, ***p < 0.001, ### p < 0.001 with the two‐way ANOVA). (E, F) The protein expression levels of eNOS and phosphorylation of eNOS (p‐eNOS) in aorta were detected by western blot. (n = 3, the data are expressed as the mean ± SD, ***p < 0.001, ## p < 0.01 with the one‐way ANOVA).

3.6. α‐MG Reversed Ang II‐Induced Vascular Remodeling

Ang II infusion increased aortic wall thickness, media to lumen ratio and collagen deposition in mice. α‐MG effectively reversed the vascular remodeling caused by Ang II‐infusion, including increased medial thickness media to lumen ratio and collagen deposition (Figure 7A–G). The expression of the Collagen I in red was increased in isolated aortic tissue of Ang II‐infused hypertensive mice. Sirius red staining and western blotting results were concordant and indicated that treatment with α‐MG markedly suppressed the expression of Collagen I in mice aorta (Figure 7H,I). In addition to Collagen I, we assessed vascular remodeling by measuring the expression of CNN1, Collagen III, and α‐SMA in the aorta. Our results showed that α‐MG can reverse the Ang II‐induced upregulation of CNN1 and the downregulation of Collagen III. However, there were no significant differences in α‐SMA expression levels between the groups (Figure 7J–L). These findings, together with the results for Collagen I, illustrate the beneficial effects of α‐MG on hypertensive vascular remodeling (Figure 8).

FIGURE 7.

FIGURE 7

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α‐mangostin reversed Ang II‐induced vascular remodeling. (A) Media thickness quantification and representative images of hematoxylin–eosin (HE) staining of paraffin‐embedded aortic sections. (B) Collagen content and representative sirius red images in aorta. The aorta sections were also imaged using polarized light microscopy to show the collagen type I (Collagen I) in red. (C–G) The quantitative analyses of relative collagen content, media thickness, lumen diameter, media‐to‐lumen ratio, and cross‐sectional area (n = 8, the data are expressed as the mean ± SD, *p < 0.05, **p < 0.01, # p < 0.05, ## p < 0.01 with the one‐way ANOVA). (H–L) The protein expression levels of Collagen I, Collagen III, CNN1, α‐SMA in aorta were detected by western blot. GAPDH was used as the internal control (n = 3, the data are expressed as the mean ± SD, *p < 0.05, **p < 0.01, # p < 0.05, ## p < 0.01 with the one‐way ANOVA).

FIGURE 8.

FIGURE 8

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Schematic diagram illustrating the signaling pathway through which α‐MG influences hypertension, hypertension‐associated vascular remodeling, and changes in uric acid levels. Inline graphic, increase; Inline graphic, decrease.

4. Discussion

The present study identified a new agent, α‐MG, which has dual effects of BP and Sua lowering. Treatment with α‐MG reduced BP, improved endothelial relaxation, and reversed aortic wall thickening and type‐I collagen deposition in Ang II‐induced hypertensive mice. Expression of AT1R and ACE in mice aorta was downregulated, while the expression of ACE2, MasR, and Ang‐(1–7) was upregulated in the α‐MG treatment groups compared with the Ang II group. As expected, α‐MG increased the Cua and markedly decreased Sua.

α‐MG has previously been a research hotspot in a variety of tumors, such as breast cancer, melanoma, leukemia, and so on. (Cruz‐Gregorio et al. 2023; Dewi et al. 2023) A recent study demonstrated that α‐MG exerted urate‐lowering effect by downregulating the expression of GLUT9 in hyperuricemic mice, but not urate anion transporter 1 (URAT1), which both are important transporters for urate reabsorption in the tubular system. (Niu et al. 2023; Novikov et al. 2019; Zhang et al. 2021) We confirmed that treatment with α‐MG downregulated GLUT9 other than URAT1 in the kidney of hypertensive mice. URAT1, localized in the apical membrane of proximal tubular epithelial cells, is a 12‐transmembrane protein urate/anion exchanger. (So and Thorens 2010) GLUT9, the basolateral 12 transmembrane protein, transports uric acid from the intracellular space to the interstitium in a voltage‐dependent manner. (Anzai et al. 2008; Auberson et al. 2018) The expression of GLUT9 is mainly in the liver and the kidney, yet that in aorta has been rarely reported. (Mobasheri et al. 2005; So and Thorens 2010) Our study has identified that GLUT9 is also distributed in mouse aorta, and we found that Ang II infusion upregulated GLUT9 expression in both kidney and aorta, while expression of other SLC family members was not altered, including Slc22a12 (encoding URAT1). This finding suggested that elevated Sua levels may partially be explained by upregulated GLUT9 in hypertensive status, which reduces uric acid excretion in kidney, and α‐MG can reduce Sua and increase the Cua, possibly by downregulating the expression of GLUT9. Further intervention studies on the target of GLUT9 is warranted.

Intriguingly, we found the hypotensive effect of α‐MG in the present study. Treatment with α‐MG at 4.0 and 8.0 mg/kg significantly attenuated Ang II‐induced hypertension. Considering current controversial views on the causal relationship between hypertension and uric acid, we further treated Ang II‐infused hypertensive mice with benzbromarone, a potent UA transporter inhibitor, at the dose of 25 mg/kg twice daily. (Gois and Souza 2017; Parsa et al. 2012) However, benzbromarone markedly reduced Sua levels in hypertensive mice, but not levels of BP, suggesting that the hypotensive effect of α‐MG might not be necessarily due to its urate‐lowering effect. Previous study demonstrated that G. mangostana pericarp extract (GME) significantly reduces L‐NAME‐induced hypertension and cardiovascular remodeling in rats. (Boonprom et al. 2017) Studies have also indicated that long‐term intake of G. mangostana rind can reduce SBP in diet‐induced metabolic syndrome rats. (John et al. 2021) However, G. mangostana rind is not only rich in xanthones such as α‐, β‐, and γ‐mangostin, but also contains a variety of active ingredients including tannins, terpenes, anthocyanins, benzophenones, depsiphone, green glucosides, polyphenols, and flavonoids. (Pedraza‐Chaverri et al. 2008; Sultan et al. 2022) Unlike previous studies that utilized extracts from GME, our research focuses specifically on α‐MG as a singular active compound. This approach allows us to directly assess the effects of α‐MG on hypertension pathways without confounding variables from other components of the extract. We employed an Ang II‐induced hypertension mouse model based on the statement from AHA, which is well‐established and widely recognized in hypertension research. This model is pivotal in studying hypertension‐related mechanisms and testing potential therapeutic interventions, providing valuable insights into α‐MG's potential as a targeted treatment for hypertension.

RAS is composed of two counter‐regulatory axes, the classical ACE/Ang II/AT1 axis (“the foe”) and the non‐classical ACE2/Ang‐(1–7)/MasR axis (“the friend”). The primary action of ACE2 is to catalyze Ang peptides to Ang‐(1–7). The ACE2‐Ang‐(1–7)‐MasR axis exerts vasodilator, antiproliferative, and anti‐inflammatory actions opposed to those of the ACE‐Ang II‐AT1R axis. (Boehm and Nabel 2002; Corvol et al. 1995) ACE /AT1 signaling was robustly upregulated by Ang II infusion for 14 days, but treatment with α‐MG reversed ACE/AT1 upregulation and enhanced the expression of ACE2/Ang‐(1–7)/MasR. Therefore, α‐MG not only blunts the effects of the classical ACE‐Ang II‐AT1R axis but also enhances its opposing axis. ACE plays a critical role in the RAS by converting angiotensin I to Ang II, a potent vasoconstrictor. In an Ang II‐induced hypertension model, administered Ang II could promote the upregulation of all components of intra‐tubular RAS including ACE. (Rivera et al. 2020) ACE activation causes more Ang I to Ang II conversion. Ang‐(1–7) is degraded by ACE into the inactive peptide. (Lubel et al. 2008) Our results showed that α‐MG treatment inhibited Ang II‐induced ACE upregulation and alleviated Ang‐(1–7) degradation. Thus, the increase in serum Ang‐(1–7) concentration may be a combination of increased production and decreased degradation. Ang‐(1–7)/MasR axis activates eNOS and promotes NO·generation to maintain vasodilation. (Savoia et al. 2020) α‐MG may reverse Ang II infusion‐induced impairment of NO‐mediated endothelium‐dependent relaxation in the aorta by activating the ACE2/Ang‐(1–7)/MasR axis, which in turn promotes eNOS expression in the aorta. A more in‐depth study, including transcriptomic analysis, could help elucidate the relevant signaling pathways involved.

It is worth noting that although the doses of 4.0 and 8.0 mg/kg of α‐MG exhibited similar antihypertensive efficacy, there were significant dose‐dependent effects on uricosuric actions and RAS. Treatment with 4.0 mg/kg α‐MG did not alter levels of AT1R and MasR expression in aorta. Meanwhile, we also demonstrated that the α‐MG treatment is well tolerated and safe in mice. Previous acute toxicology experiments also showed that α‐mangostin had a good safety without toxic reactions in mice at a dose of 5 g/kg. (Niu et al. 2023) No mortalities, body weight loss, abnormal behaviors, and heart rate fluctuations were observed.

Even though we first reported the hypotensive effect of α‐MG on Ang II‐infused hypertensive mice, its efficacy in other hypertensive animal models remains to be further investigated. α‐MG has poor aqueous solubility (2.03 × 10−4 mg/L at 25°C), which might limit the possibility of in vitro study. (Wathoni et al. 2020) Previous research has demonstrated that α‐MG can be dissolved in dimethyl sulfoxide (DMSO) or methanol for in vitro experimentation. (Kim et al. 2023) Future research may explore these methods and determine the optimal concentrations of α‐MG for in vitro investigations.

Furthermore, considering the predominant expression of GLUT9 in the liver and kidney, it is imperative to investigate the impact of α‐MG on GLUT9 in these specific organs. A comprehensive dose–response analysis is warranted to ascertain the optimal dosage of α‐MG for achieving therapeutic benefits while mitigating potential adverse effects. The integration of α‐MG with other pharmacological agents with synergistic mechanisms of action may offer a promising therapeutic approach. By employing lower dosages of each agent in combination, it is plausible to achieve the desired therapeutic outcome while minimizing the risk of adverse reactions. (Xu et al. 2023) The direct clinical effects of α‐MG were not evaluated in the present study, but our findings suggest that a dosage of α‐MG 8.0 mg/kg twice daily effectively reduced BP and reversed vascular remodeling in a mouse model of Ang II‐induced hypertension. The observed decrease in BP of approximately 20 mmHg with α‐MG at 8.0 mg/kg twice daily was similar to the effects of irbesartan (50 mg/kg/day) and amlodipine (10 mg/kg/day). (Zhong et al. 2020) According to the dose conversion tables proposed by Nair and Jacob (2016), the equivalent dose for α‐MG 8.0 mg/kg twice daily in mice approximates 1.3 mg/kg/day in human (50 kg), which might be utilized as a reference for establishing an appropriate dosage in human trials. It is imperative to recognize that this calculated dose is subject to modification following additional pharmacokinetic and pharmacodynamic analyses, as well as safety and efficacy assessments from early‐stage clinical trials.

5. Conclusion

Hyperuricemia is a common comorbidity of hypertension and probably has a causal relationship with hypertension. Treatment with α‐MG reduced BP, improved endothelial relaxation, and reversed aortic wall thickening and type‐I collagen deposition in Ang II‐induced hypertensive mice. Expression of AT1R and ACE in mice aorta was downregulated, while the expression of ACE2, MasR, and Ang‐(1–7) was upregulated in the α‐MG treatment groups compared with the Ang II group. As expected, α‐MG increased the Cua and markedly decreased Sua. α‐MG, with both excellent antihypertensive effects and hypouricemic effects, may become a novel drug candidate for hypertensive patients, especially those concomitant with hyperuricemia.

Author Contributions

Qi‐Qi Xue: investigation, methodology, writing – original draft, writing – review and editing. Chu‐Hao Liu: data curation, methodology, writing – review and editing. Dong‐Yan Zhang: project administration, validation. Ming‐Xuan Li: validation. Yan Li: funding acquisition, project administration, writing – review and editing.

Ethics Statement

Approval was acquired for all experiments involving animals from Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1. Supporting Information.

PTR-38-5918-s001.docx (567.1KB, docx)

Acknowledgments

This research was supported by funding from the National Natural Science Foundation of China (82270649, 82100445, and 82070432), Natural Science Foundation of Shanghai (22ZR1452900), Shanghai Sailing Program (21YF1438700), and Shanghai Leading Academics (2022LJ022).

Funding: This research was supported by funding from the National Natural Science Foundation of China (82270649, 82100445, and 82070432), Natural Science Foundation of Shanghai (22ZR1452900), Shanghai Commission of Science and Technology (Shanghai‐Sailing‐Program‐21YF1438700), and Shanghai Commission of Health (Shanghai‐Leading‐Academics‐2022LJ022).

Qi‐Qi Xue, Chu‐Hao Liu, and Dong‐Yan Zhang are co‐first authors.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1. Supporting Information.

PTR-38-5918-s001.docx (567.1KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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