ABSTRACT
Background
Anthocyanin plays a protective role in cardiovascular disease through antioxidant effect. Whether anthocyanin can reduce salt-induced hypertension and the related mechanisms remain unclear.
Methods
Chronic infusion of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or anthocyanin (10 mg/kg, 0.4 μL/h) into bilateral paraventricular nucleus (PVN) of Sprague-Dawley rats was performed. Then, the rats were fed a high salt diet (8% NaCl, HS) or normal salt diet (0.9%, NaCl, NS) for 4 weeks.
Results
High salt diet induced an increase in blood pressure and peripheral sympathetic nerve activity (increased LF/HF and decreased SDNN and RMSSD), which was accompanied by increased reactive oxygen species (ROS) production and angiotensin II type-1 receptor (AT1R) expression and function in the PVN. Moreover, the NOD-like receptor protein 3 (NLRP3) and related inflammatory proteins (caspase-1) expression, the pro-inflammatory cytokine levels including IL-1β and TNF-α were higher in PVN of rats with a high salt diet. Bilateral PVN infusion of anthocyanin attenuated NLRP3-dependent inflammation (NLRP3, caspase-1, IL-1β and TNF-α) and ROS production, reduced AT1R expression and function in PVN and lowered peripheral sympathetic nerve activity and blood pressure in rats with salt-induced hypertension.
Conclusions
Excessive salt intake activates NLRP3-dependent inflammation and oxidative stress and increased AT1R expression and function in the PVN. Bilateral PVN infusion of anthocyanin lowers peripheral sympathetic nerve activity and blood pressure in rats with salt-induced hypertension by improvement of expression and function of AT1R in the PVN through inhibiting NLRP3 related inflammatory and oxidative stress.
Hypertension is the result of the interaction between environmental factors and genetic factors (Citation1). Among the environmental factors, high salt intake is a common and controllable dietary risk factor. The World Health Organization recommends an amount of dietary salt intake <5 g/d, but the average salt intake is 10.5 g/d in China (Citation2)2. In 2017, more than 3 million deaths worldwide are linked to high-salt diets, and China accounted for half of those deaths (Citation2). Although some measures to limit salt intake are in place, the incidence and mortality of salt-induced hypertension have not been significantly reduced. In particular, some patients with salt-induced hypertension are resistant to general antihypertensive drugs. Therefore, it is important to clarify the pathogenesis of salt-induced hypertension for its effective treatment.
High salt can induce hypertension through various mechanisms acting on different organs (Citation3). Previous studies have shown that high salt intake activates the renin angiotensin aldosterone system (RAAS) (Citation4) and inhibits the dopamine (Citation5) and prostaglandin-related systems (Citation6) in the kidney, leading to sodium retention, in turn, elevated blood pressure. In addition, high salt can also trigger inflammation and oxidative stress, cause vascular endothelial cell damage and reduce endothelial oxide synthase activity and production of NO, which leads to vascular systolic and diastolic dysfunction (Citation7). In the brain, high salt diet induces the change of the glutamate/GABA-glutamine metabolic cycle via the gut-brain axis and an increase in NADPH-oxidase activity, leading to increased blood pressure (Citation8). Studies have shown that the paraventricular nucleus (PVN) is the initiating site of salt-induced hypertension (Citation9). Improving the level of inflammation and oxidative stress in the PVN can significantly inhibit the excitability of neurons in the PVN, thus reducing peripheral sympathetic nerve activity and lowering blood pressure (Citation10).
Anthocyanin belongs to bioflavonoids, widely distributed in fruits, vegetables and flowers, with free radical scavenging and antioxidant effects (Citation11). Anthocyanin could protect the neurovascular unit through inhibiting NF-κB and NLRP3 inflammasome pathway in cerebral ischemia/reperfusion injury (Citation12). Wine lees powder from a Cabernet grape variety with high content of anthocyanin has antihypertensive effects, and the mechanism is related to the activation of Sirt1 to improve vascular endothelium-dependent diastole response (Citation13). However, to date, the underlying molecular mechanism by which anthocyanin lowers blood pressure remains elusive. Therefore, we hypothesized that high salt induced inflammation and oxidative stress in the PVN of the hypothalamus, which in turn promoted RAS activation, resulting in enhanced peripheral sympathetic nerve activity, and anthocyanin infusion to the PVN could reverse these abnormalities and lower blood pressure.
Materials and methods
Animal
Male Sprague-Dawley rats weighing (180–200 g) at the age of 12 weeks were purchased from the Animal Centre of Army Medical University. All animals were housed in temperature- and light-controlled animal quarters and had free access to standard rodent chow and drinking water. The study was conformed to the National Institutes of Health guidelines, and the protocols were approved by the Animal Care and Use Committee of Army Medical University.
Experimental protocol
To determine the effect of anthocyanin on lowering blood pressure through the PVN, all rats were implanted bilaterally with PVN with sterilizing cannulas, as described previously. The osmotic minipumps (2006, Alzet Model) were implanted subcutaneously and connected to the PVN cannulae. The rats were randomly divided into control and anthocyanin treatment groups. Control group was infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h, Sigma, MO, USA), and anthocyanin treatment group was infused with anthocyanin (10 mg/kg, 0.4 μL/h, Sigma) into the bilateral PVN of rats. Then, those two groups were, respectively, fed with 8% high salt diet (8% NaCl, HS) and 0.9% normal salt diet (0.9%, NaCl, NS) for 4 weeks. To observe the role of AT1 receptor in PVN in mediating peripheral sympathetic activation, AT1 receptor inhibitor (Losartan, 11.45 nmol/kg, Sigma) was injected into PVN as a bolus injection at the age of 16 weeks.
Blood pressure and heart rate measurement
Blood pressure and heart rate were measured once weekly for 4 weeks using a CODA noninvasive tail-cuff system (BP-98A; Softron, Tokyo, Japan), as described previously. Before blood pressure was measured, the rats were placed on a 37°C heating table, and their tails were heated for 5 min. Blood pressure, heart rate and body weight were measured three times and the average value was taken.
Heart rate variability measurement
Peripheral sympathetic nerve activity was determined by heart rate variability (HRV) including low-frequency and high-frequency ratio (LF/HF), standard deviation of the N-N intervals (SDNN) and square root of the mean squared differences of successive N-N intervals (RMSSD), using the Powerlab ECG system (AD Instruments, Australia) and Chart 7.0 software.
Inflammatory and oxidative stress markers measurement
Inflammatory markers including IL-1β and TNF-α and oxidative stress markers including MDA and GSH in PVN were measured by ELISA kit (Beyotime Institute of Biotechnology, Shanghai, China). The detailed methods were described in previous studies (Citation14).
Analysis of AngII concentration
Ang II concentrations in tissue from PVN were measured by using enzyme immunoassay kit (Cloud Clone, Wuhan, China).
Dihydroethidium staining
Dihydroethidium (DHE, Beyotime) staining was used to measure the level of reactive oxygen species in PVN of rats. In brief, the brain tissue was taken out and the tissue was implanted with OCT embedding solution and sliced continuously by freezing microtome. After rinsing the vascular rings on the slides for three times with phosphate buffer solution (PBS), DHE (10 μmol/L) was added, and the samples were placed at room temperature for 30 min. Finally, they were washed again with PBS for three times and images were taken with a fluorescence microscope.
Western blot analysis
The protein expressions of related genes in PVN were determined by western-blot, as reported in previous studies (Citation15). In brief, PVN tissue samples were extracted and homogenized using ice-cold RIPA lysis buffer for 2 h. After the protein concentration was measured, the protein loading buffer was added and boiled for 5 min to fully denature the protein. The proteins were electrophoresed by SDS-polyacrylamide gels and electroblotted onto nitrocellulose membranes. The blots were incubated with primary polyclonal antibodies for anti-NLRP3 (1:300, Abcam, Cambridge, UK), anti-caspase-1 (1:300, Abcam), anti-AT1R (1:300, Abcam) and anti-GAPDH (1:500, Abcam) at 4°C overnight. After the membranes were washed, blots were incubated with secondary antibody (1:10000, Li-Cor Biosciences, NE, USA) labeled with horseradish peroxidase for 1 h at room temperature. The immunoreactive bands were detected using enhanced chemiluminescence, and the images were analyzed using ImageJ software.
Statistical analysis
The data were expressed as mean ± SEM. Statistical analysis was performed using the GraphPad Prism 5.0 software. Data were analyzed by one-way ANOVA followed by Newman–Keuls post hoc test whenever appropriate. Value of P < .05 was considered significant.
Results
Anthocyanin lowered elevated blood pressure and heart rate in salt-induced hypertension
Compared with a normal salt diet, a high salt diet induced significant increases in blood pressure including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate in rats. Anthocyanin treatment significantly reduced salt-induced increases in blood pressure and heart rate (). However, anthocyanin treatment had no significant effect on blood pressure and heart rate in rats with a normal salt diet (). In addition, body weight was also measured and no significant difference in body weight was found among the groups ().
Figure 1. Effect of anthocyanin by chronic bilateral PVN infusion on blood pressure and heart rate in rats with salt-induced hypertension. The rats fed 8% high salt diet (HS) and the rats fed 0.9% normal salt diet (NS) were treated with vehicle (aCSF, 0.4 μL/h) or anthocyanin (10 mg/kg, 0.4 μL/h) into the bilateral PVN of rats. Systolic blood pressure (SBP) (a) and diastolic blood pressure (DBP) (b) were measured from 12 to 16 weeks of age by tail-cuff plethysmography. Data were expressed as the means ± S.E.M (n = 6/group). *P < .05 vs NS+aCSF or NS+anthocyanin; #P < .05 vs HS+aCSF. (c and d) Heart rate and body weight were measured in 16-week-old rats. *P < .05 vs others.
Anthocyanin lowered the hyperactivity of SNS in salt-induced hypertension
As indicated above, a high salt diet induced a significant increase in heart rate in rats, indicating sympathetic activation in high salt-induced hypertension. In addition, we assessed the levels of peripheral sympathetic nerve activity by measuring HRV, providing further evidence for sympathetic nerve activation. Compared with a normal salt diet, LF/HF was increased, and SDNN and RMSSD were decreased in rats with a high salt diet. However, anthocyanin treatment inhibited sympathetic nerve activation via reducing the level of LF/HF and increasing the levels of SDNN and RMSSD in high salt-induced hypertension (). Anthocyanin treatment had no significant effect on HRV in rats with a normal salt diet ().
Figure 2. Effect of anthocyanin by chronic bilateral PVN infusion on heart rate variability (HRV) in rats with salt-induced hypertension. The rats fed 8% high salt diet (HS) and the rats fed 0.9% normal salt diet (NS) were treated with vehicle (aCSF, 0.4 μL/h) or anthocyanin (10 mg/kg, 0.4 μL/h) into the bilateral PVN of rats. HRV parameters including LF/HF (A), SDNN (b) and RMSSD (c) were measured by Powerlab ECG system at 16 weeks of age. Data were expressed as the means ± S.E.M (n = 6/group). *P < .05 vs others.
Anthocyanin lowered the expression and function of AT1R in the PVN of rats with salt-induced hypertension
RAAS system components in PVN, especially AT1R, are one of the most important factors in regulating peripheral sympathetic nerve activity (Citation16). Compared with a normal salt diet, a high salt diet induced increased AT1R expression and Ang II levels in PVN () and the microinjection of losartan, an AT1R blocker in PVN lowered LF/HF and SBP of rats with a high salt diet (). Anthocyanin treatment reduced AT1R expression and Ang II levels in PVN of rats with salt-induced hypertension and inhibited losartan-mediated the reduction of LF/HF and SBP of rats with a high salt diet (), indicating anthocyanin treatment reversed the increased expression and function of AT1R in the PVN of rats with salt-induced hypertension.
Figure 3. Effect of anthocyanin by chronic bilateral PVN infusion on the expression and function of AT1R in the PVN of rats with salt-induced hypertension. The rats fed 8% high salt diet (HS) and the rats fed 0.9% normal salt diet (NS) were treated with vehicle (aCSF, 0.4 μL/h) or anthocyanin (10 mg/kg, 0.4 μL/h) into the bilateral PVN of rats. (a and b) AT1R expression was detected by western-blot and Ang II levels in PVN were measured by ELISA kit. (c and d) Effect of the AT1R receptor antagonist, losartan, on LF/HF and blood pressure in rats with or without anthocyanin treatment. Data were expressed as the means ± S.E.M (n = 6/group). *P < .05 vs others.
Anthocyanin reduced the levels of NLRP3-related inflammation in the PVN of rats with salt-induced hypertension
Neuroinflammation in the PVN is closely related to the increased AT1R expression and function in rats with hypertension (Citation17). We assessed the levels of NLRP3-related inflammation in PVN and found that compared with a normal salt diet, the expressions of NLRP3 and its downstream caspase-1 were enhanced in rats with a high salt diet (). Moreover, the pro-inflammatory cytokine levels including IL-1β and TNF-α were higher in PVN of rats with a high salt diet (. Anthocyanin treatment could reverse the abnormal expression levels of the above inflammatory marker in rats with a high salt diet ().
Figure 4. Effect of anthocyanin by chronic bilateral PVN infusion on the NLRP3-related inflammation in the PVN of rats with salt-induced hypertension. (a, A1 and A2) NLRP3 and caspase-1 expression was detected by western-blot. (b and c) the pro-inflammatory cytokine levels including IL-1β and TNF-α were measured by ELISA. Data were expressed as the means ± S.E.M (n = 6/group). *P < .05 vs others.
Anthocyanin alleviated oxidative stress in the PVN of rats with salt-induced hypertension
Oxidative stress is also an important mediator of increased AT1R receptor and function in PVN of hypertensive rats (Citation18). We found that compared with a normal salt diet, ROS levels in PVN of rats with a high salt diet were higher, which were reversed by anthocyanin treatment (). In addition, we further measured MDA and GSH levels in the PVN and found that compared with a normal salt diet, MDA level was increased and GSH level was decreased in PVN of rats with a high salt diet ). Anthocyanin treatment reduced oxidative stress including decreased MDA and increased GSH level in PVN of rats with a high salt diet ().
Figure 5. Effect of anthocyanin by chronic bilateral PVN infusion on the oxidative stress in the PVN of rats with salt-induced hypertension. (a and A1) ROS in PVN was detected by DHE staining. (b and c) MDA and GSH levels in PVN were measured by ELISA. Data were expressed as the means ± S.E.M (n = 6/group). *P < .05 vs others.
Discussion
Long-term high salt induced organ inflammation and oxidative stress, contributing to cardiovascular damage, which leads to salt-related hypertension (Citation19) and atherosclerosis (Citation20), etc. Among them, with the change of people’s diet structure, the incidence of salt-induced hypertension is increasing. At present, effective treatment of salt-induced hypertension is the key to reduce related cardiovascular complications. Although most antihypertensive drugs have certain clinical effects on salt-induced hypertension, some patients still have poor effects when using multiple antihypertensive drugs, and the reasons are worth further research and exploration.
The mechanisms of salt-induced hypertension are complex, including abnormal renal sodium ion transport channels (Citation21), activation of sympathetic (Citation22) and RAAS (Citation4), vascular endothelial dysfunction (Citation23) and vascular smooth muscle remodeling (Citation24). Recently, more and more attention has been paid to the role of PVN of hypothalamus in the occurrence of hypertension (Citation25). Some studies have reported that the reason for poor antihypertensive treatment in some hypertensive patients is related to the abnormal cardiovascular regulatory center of PVN (Citation26). The intervention of the brain center, especially the PVN, may be one of the important targets for treatment of hypertension. Previous studies have found that high salt can induce increased oxidative stress and inflammation (Citation27), decreased neuropeptide Y expression (Citation28), the inhibition of brain Na+/K+-ATPase (NKA) activity (Citation29), and microglia activation (Citation30) in the PVN. Among them, inhibition of inflammation and oxidative stress in PVN is an important therapeutic strategy to reduce local neuronal excitability, thus inhibiting peripheral sympathetic nerve activity and reducing blood pressure. In our present study, consistent with previous study of others (Citation31), we found that high-salt diet induced increased blood pressure in rats, accompanied by increased peripheral sympathetic nerve activity. Peripheral sympathetic nerve activity is mainly regulated by neurons in the central PVN, which can be divided into excitatory and inhibitory neurons (Citation32). Local inflammation and oxidative stress can activate excitatory neurons and promote the increase of excitatory neurotransmitters, thus increasing peripheral sympathetic nerve activity and blood pressure (Citation33). We found that high-salt diet induced activation of the NLRP3 inflammasome in PVN, promoting downstream inflammatory pathways and oxidative stress. Inhibition of NLRP3 in PVN can reduce blood pressure in hypertensive rats (Citation34) and improve myocardial remodeling after myocardial infarction in mice (Citation35).
A large number of studies have demonstrated that anthocyanin plays an anti-tumor (Citation36), cardiovascular protection (Citation37) and anti-aging (Citation38) role by inhibiting inflammation and oxidative stress. Anthocyanin induces eNOS expression and escalated NO production via a Src-ERK1/2-Sp1 signaling pathway to ameliorate endothelial dysfunction, harmonize blood pressure and prevent atherosclerosis (Citation39). Whether anthocyanin can lower salt-induced hypertension and its related mechanism is not clear. In our present study, we found that anthocyanin can significantly inhibit the activation of NLRP3 inflammasome in PVN of rats with salt-induced hypertension, thereby reducing local inflammation and oxidative stress. The PVN is a cardiovascular regulatory center that can express components of RAAS. The high expression of AT1R is an important mechanism to promote the activation of excitatory neurons (Citation15). Previous studies have shown that chronic bilateral PVN infusion of AT1R receptor antagonists can significantly lower the activity of peripheral sympathetic nerve, improve blood pressure and vascular and myocardial remodeling (Citation40). In our study, we found that high salt diet induced increased AT1R expression in PVN and anthocyanin treatment reduced AT1R expression, which contributes to lower the peripheral sympathetic activity and salt-induced hypertension.
This study has the following limitation: first, how anthocyanin reduces the expression of NLRP3 inflammasome in the PVN of salt-induced hypertensive rats. Second, anthocyanin has antioxidant effects. The improvement of expression and function of AT1R in the PVN of salt-induced hypertensive rats could be partly due to the antioxidant effect of anthocyanin. Previous studies have reported that anthocyanin is associated with blood pressure regulation, directly or indirectly by other mechanisms. Anthocyanin has been shown to increase endothelial-derived nitric oxide, which in turn prevents vascular smooth muscle contraction (Citation41). Furthermore, anthocyanin has been shown to reduce the synthesis of vasoconstricting molecules, such as Ang II and endothelin-1 via inhibition of the cyclooxygenase pathway (Citation42).
In conclusion, we provided evidence that sympathetic nervous activation is one of the important mechanisms of salt-induced hypertension and anthocyanin treatment reduced sympathetic activity and blood pressure by improvement of expression and function of AT1R in the PVN through inhibiting NLRP3 related inflammatory and oxidative stress.
Author contribution
CX and JZ conceived and designed the experiments and wrote the manuscript; ZZ performed the experiments and analyzed the data; GG revised the manuscript; YZ and LG provided the project funding; CM approved the final version of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
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