The effects and mechanisms of quercetin on blood pressure, gut microbiota, and ventricular remodeling in spontaneously hypertensive rats
At present, the incidence and mortality rates of cardiovascular disease in China are still increasing. According to research, the current number of cardiovascular disease patients in China is estimated to be 290 million, of which 245 million are suffering from hypertension, which is also a major risk factor for cardiovascular disease and brings a heavy burden to families and the country. More and more studies have found that hypertension is related to intestinal microbiota imbalance, but its specific mechanism is still unclear and needs further research. Current research has shown that Toll like receptor 4 (TLR4) is associated with hypertension and ventricular remodeling. The main ligand for TLR4 is lipopolysaccharides, and TLR4 binding to ligands can activate nuclear factor kappa B (NF – κ B), leading to the release of inflammatory factors and promoting endothelial cell inflammatory damage, vascular dysfunction, and remodeling, participating in ventricular remodeling. And dysbiosis of gut microbiota can catalyze immune responses. Quercetin is a flavonoid compound widely present in flowers, leaves, and fruits of plants. Existing studies have shown that quercetin has effects such as lowering blood pressure, antioxidant, anti-inflammatory, and regulating immune function. At present, there is limited research on the effect of quercetin on hypertensive ventricular remodeling through gut microbiota. This experiment aims to investigate the effects and mechanisms of quercetin on blood pressure, gut microbiota, and ventricular remodeling in spontaneously hypertensive rats (SHR).

In this experiment, 8 Wistar Kyoto rats were used as the control group (WKY), and 24 SHRs were randomly divided into a model group (SHR), a benazepril group (Ben), and a quercetin group (Que). They were orally administered and blood pressure was measured. After 8 weeks, serum Toll like receptor 4 (TLR4) and NF – κ B p65 concentrations were detected by ELISA, and gut microbiota was detected by 16S-V4 sequencing; Calculate the cardiac mass index and left ventricular mass index, observe myocardial fibrosis using the picric acid fuchsin staining method, and calculate CVF; Western blot and RT-PCR were used to detect the levels of TLR4 protein and mRNA in myocardial tissue.

Hypertension is a common and frequently occurring disease in China, which is the result of multiple factors such as genetics and environment. It is an important risk factor for cardiovascular and cerebrovascular diseases and can damage important organs such as the heart, brain, and kidneys, leading to multiple organ failure. Hypertension and excessive cardiac pressure load, as well as activation of the renin-angiotensin aldosterone system, can stimulate myocardial cell hypertrophy and interstitial fibrosis, leading to left ventricular hypertrophy and dilation, ventricular remodeling, further causing myocardial ischemia, heart failure, etc. Bringing a heavy economic burden to families and the country. SHR has a disease development process similar to human primary hypertension. Ventricular remodeling includes myocardial hypertrophy and myocardial fibrosis. The left ventricular mass index can reflect myocardial hypertrophy, while CVF can reflect myocardial fibrosis. Previous studies have shown that quercetin has important physiological effects such as anti-inflammatory, free radical scavenging, and vasodilation. This experiment used the SHR model to investigate the effects and mechanisms of quercetin on blood pressure, ventricular remodeling, and gut microbiota.

The results of this study showed that SHR had higher blood pressure, heart mass index, left ventricular mass index, and CVF compared to WKY, indicating ventricular remodeling. After treatment with quercetin in spontaneously hypertensive rats, blood pressure decreased and cardiac mass index, left ventricular mass index, and CVF improved, indicating that quercetin can lower blood pressure and improve ventricular remodeling. But its effect is weaker than that of the angiotensin-converting enzyme inhibitor benazepril. However, the CVF values of each group were relatively small. After intervention with quercetin, it was observed that CVF improved compared to SHR, but the difference was not statistically significant. Considering that the sample size may be relatively small and related to drug intervention time, further research can be conducted by increasing the sample size or prolonging the drug intervention time.

At present, it has been confirmed through animal models and clinical studies that the gut microbiota and its metabolites are involved in the occurrence and development of hypertension. Therefore, intervening in the gut microbiota to treat hypertension is expected to become a potential therapeutic target for hypertension. But its specific mechanism needs further research. At present, research has found that the human gut microbiota is mainly composed of Firmicutes and Bacteroidetes. Dysbiosis of gut microbiota is characterized by abnormal functional and structural ratios of gut microbiota, commonly measured by F/B. Previous studies have found that spontaneously hypertensive rats, angiotensin II induced hypertensive rats, and hypertensive patients exhibit gut microbiota dysbiosis, with significantly increased F/B and decreased gut microbiota richness and diversity. After transplanting the cecal contents of WKY into SHR, there was a decrease in blood pressure, but it was not statistically significant; After transplanting the cecal contents of stroke prone SHR to WKY, the latter’s blood pressure increased and F/B significantly increased. Recent studies have shown that after transplanting feces from hypertensive patients into sterile mice, their blood pressure increased, indicating that gut microbiota plays a crucial role in the development of hypertension. The results of this study showed that the F/B ratio of SHR was higher than that of WKY, and the richness of gut microbiota was significantly reduced with statistical significance. The diversity of gut microbiota was also reduced, but the difference was not statistically significant. It is considered that the sample size can be increased for further research. After treating spontaneously hypertensive rats with quercetin in this study, the F/B values of the rats decreased, and the richness and diversity of intestinal microbiota were improved, which was comparable to the effect of benazepril. This indicates that quercetin has a regulatory effect on gut microbiota, which may further lower blood pressure and improve ventricular remodeling by modulating gut microbiota.

TOLL like receptors are a family of receptors expressed on cell membranes that the immune system recognizes microorganisms and mediates both innate and acquired immunity. In mammals, TLRs are synthesized and transported in the endoplasmic reticulum to plasma or endosomal membrane cells. TLR is highly expressed in cardiomyocytes, with TLR4 being associated with primary hypertension. The main ligand of TLR4 is lipopolysaccharides. When TLR4 binds to its ligand, it can activate NF – κ B, leading to a large release of inflammatory factors and promoting the inflammatory response. Endotoxins are substances containing lipopolysaccharides produced by Gram negative (G -) bacteria. Imbalance of gut microbiota can increase the amount of endotoxins entering the bloodstream, triggering immune inflammatory reactions. Cani et al.’s study showed that under a high-fat diet, the intestinal production of lipopolysaccharides by G-bacteria increases, triggering systemic inflammation. A study has found that activating TLR4 can lead to elevated blood pressure, low-grade inflammatory response, and vascular dysfunction. The TLR4/NF – κ B pathway is a key pathway for hypertension and vascular inflammation. In TLR4 deficient mice, the increase in reactive oxygen species levels and NADPH oxidase activity induced by angiotensin II was significantly reduced, but had no effect on blood pressure. Angiotensin II stimulates TLR4 through angiotensin II type 1 receptors, producing inflammatory cytokines and oxidative stress, affecting blood vessels, kidneys, and central nervous system to promote hypertension. There are also studies showing that NF – κ B inhibitors not only inhibit the activation of NF – κ B, but also reduce the expression of TLR4 and AngII content. TLR4/NF – κ B mediated inflammatory signaling and oxidative stress are involved in the occurrence and development of left ventricular remodeling. Eisler et al. found that conventional doses of ramipril can only lower blood pressure in hypertensive rats and have no effect on the expression of TLR4 in the myocardium, while high doses not only lower blood pressure but also reduce the expression of TLR4 in the myocardium, indicating that the decrease in TLR4 expression may not only depend on the decrease in blood pressure, but also be due to the direct effect of the drug on it. Studies have shown that in high-fat diet induced non-alcoholic fatty liver disease mice, quercetin can improve F/B values, alleviate dysbiosis, downregulate TLR4/NF – κ B expression in the liver, and play a protective role in the liver. Quercetin can downregulate the TLR4/NF – κ B signaling pathway mediated by lipopolysaccharides by enhancing the expression of Toll interacting proteins. The results of this experimental study showed that quercetin can downregulate the expression of TLR4 and NF – κ B p65 in SHR serum, and downregulate the expression of TLR4 protein and mRNA in myocardial tissue. The results of this study suggest that quercetin may improve intestinal microbiota, reduce lipopolysaccharide production, downregulate TLR4/NF – κ B p65 expression, alleviate immune inflammatory responses, thereby improving vascular dysfunction and remodeling, and ultimately lowering blood pressure and improving ventricular remodeling.

In summary, this experiment demonstrated that quercetin intervention in SHR can lower blood pressure and improve ventricular remodeling, possibly by regulating gut microbiota and downregulating the TLR4/NF – κ B pathway. This provides a certain experimental basis for the clinical application of quercetin.