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Received: 11 April ; Accepted: 6 November ; Published: 16 November Another meta-analysis which included participants across 17 RCTS mirrored the results obtained by Serban et al.

More recently, a meta-analysis of 8 RCTs conducted among patients with metabolic syndrome traits showed that quercetin supplementation significantly reduced systolic BP, yet did not affect diastolic BP Clearly, trials directly comparing different doses and regimen durations are needed.

The accumulation of SCs in the aging and diseased vessel wall raises the possibility that reducing senescence might delay deterioration of vascular structure and function. In an elegant and seminal experiment, Baker et al.

demonstrated that the health span in progeroid mice can be enhanced by killing SCs using a transgenic suicide gene Elimination of SCs also delayed progression of multiple age-related phenotypes, such as cancer, cataract, sarcopenia, lordokyphosis, loss of adipose tissue and skeletal muscle fibers, as well as improved exercise capacity Based on the knowledge that SCs survive despite their harsh internal state, the hypothesis was that this would be achieved by targeting their survival pathways and anti-apoptotic mechanisms An alternative strategy to interfere with senescence would be to reduce the burden of SASP.

The advent of antibody-based techniques such as sandwich enzyme-linked immunosorbent assay, and large-scale molecular biology techniques such as mRNA profiling, antibody arrays, proteomics or multiplex assays have made the detection and measurement of several SASP factors possible These powerful tools therefore serve to test pharmaceutical efficacy of drugs that target SASP In the following sections, we will see evidence suggesting that quercetin eliminates SCs and reduces the SASP.

In , quercetin was reported to increase longevity of worms , but it was not until that its potential as a senolytic was highlighted in Kirkland's laboratory Table 1.

First, the investigators identified a series of senolytic transcripts on pre-adipocytes. These included components of the ephrin regulating system, ephrin ligands B EFNB , as well as the plasminogen-activated inhibitor-1 PAI-1 and a member of the phosphatidylinositol-4,5-bisphosphate 3 kinase PI 3 K family, involved in regulating multiple cellular functions including survival Then, they tested whether drugs that target any of these gene products would effectively induce apoptosis in radiation-induced senescent human pre-adipocytes and HUVECs.

Of the 46 agents tested, quercetin and dasatinib, a non-specific tyrosine kinase inhibitor used for cancer therapy, were noticeably promising Dasatinib is known to block EFNB-dependent suppression of apoptosis, while quercetin inhibits PI 3 K, other kinases and PAI-1, from the SERPIN family member , In contrast to dasatinib, which was more effective on pre-adipocytes, quercetin preferentially reduced viability of senescent HUVECs Parallel cultures of non-senescent HUVECs proliferated 2- to 3-fold in the presence of quercetin over the same period of 3 days, indicating that quercetin's induction of apoptosis is selective to SCs This suggests that using a mix of senolytics to target a broader range of anti-apoptotic networks may be a strategy to follow in developing future senolytic therapies Used in vivo , the senolytic cocktail also reduced the number of ppositive SCs in fat and liver from old mice Similar results were obtained by Xu et al.

This was neither associated with an increased physical morbidity nor an increased age-related disease burden Sirt1 was found to delay both replicative and stress-induced senescence Hwang et al. conducted in vitro experiments with adult human coronary artery endothelial cells HCAEC from three deceased female donors using replicative senescence as a relevant model for human arterial aging Contrary to the previous results reported in HUVECs , their findings showed that quercetin induces death in both early non-senescent and late-passage senescent HCAECs, without any selectivity for the latter Quercetin's cytotoxicity was evident in all three donors at a concentration of 10 μM, which was half the amount used with HUVECs Late-passage cells were more sensitive to quercetin's toxic effects as their relative cell abundance was already significantly decreased at a concentration of 6 μM Their study also investigated hyperoside, also known as quercetin 3-D-galactoside, as an alternative to quercetin Hyperoside is a natural derivative of quercetin produced by St.

John's Wort and structurally identical except for a galactoside group attached in position 3 Figure 2 In contrast to quercetin, hyperoside had no significant cytotoxicity to either proliferating or late-passage HCAECs but was unable to display any senolytic activity A second in vitro model of an adult human vasculature model was investigated by Jiang et al.

using human aortic endothelial cells HAECs In their study, senescence was induced by ox-LDLs. Their results revealed that quercetin decreased the expression of senescence-associated β-galactosidase and improved cell morphology of HAECs The senolytic effect was dose dependent, as 0.

Quercetin simultaneously decreased ROS generation, also in a concentration-dependent manner. In addition, transcriptome microarray assays were performed and identified differentially expressed genes in the mRNAs profile of senescent HAECs treated with quercetin Among them, several were involved in p53 and mammalian target of rapamycin mTOR signaling pathways, NO metabolism, maintenance of the cytoskeleton, extracellular matrix-receptor interaction, as well as complement and coagulation cascades, suggesting the potential mechanisms by which quercetin was effective against ox-LDLs Quercetin also decreased the genetic expression of AATK, CDKN2A , and IGFBP3 AATK is induced during apoptosis, while CDKN2A p16 is one of the most important senescence markers Interestingly, a high circulating concentration of IGFBP3 was found to be a predictor of IHD One can therefore wonder if quercetin could alleviate the risks of IHD in patients by decreasing IGFBP3.

Clinical trials studying the senolytic effects of quercetin remain scarce Table 1. Another open label pilot study was conducted by Hickson et al. in 9 adults aged 50—80 years with diabetic kidney disease The patients received a 3 day oral treatment regimen with dasatinib mg daily and quercetin mg bid.

Eleven days after treatment completion, there was a significant reduction in the number of adipose tissue SCs and circulating SASP factors, including IL-1α, IL-6, MMP-9, and MMP, accompanied by an increase of adipocyte progenitors, suggesting a selective cytotoxic effect for SCs These results are in agreement with a previous in vitro study performed on human omental tissue resected during gastric bypass surgery To the best of our knowledge, no clinical trial has yet examined the senolytic effects of quercetin on endothelial dysfunction in humans, in the context of CVD.

The beneficial effects of quercetin on dyslipidemia, hypertension, senescence and other risk factors can be seen as a primary prevention measure against endothelial dysfunction.

Once the endothalial dysfunction has resulted in an adverse cardiac event, secondary and tertiary prevention strategies become crucial in order to reduce the progression of the disease and its impacts on patients' quality of life.

One of the most striking examples is myocardial ischemia. In the latter, dysfunctional endothelial cells of the coronary arteries induce a local disturbance in other cell lines, including cardiomyocytes and fibroblasts They trigger a host response which includes increased oxidative stress, calcium imbalance, as well as cytokine, platelets, and leukocytes activation This endothelial dysfunction is also a critical mediator of myocardial dysfunction after reperfusion In response, many pathological adaptations occur, such as increased extracellular matrix deposition leading to myocardial interstitial fibrosis, changes in the myocardial cell morphology, and eventually, ventricular dilatation Clinically, it translates into debilitating conditions, ranging from stable angina to myocardial infarction and heart failure.

In addition, experimental data showed that endothelial dysfunction correlates with the degree of myocardial injury, both from the ischemic and reperfusion insults These observations suggest that quercetin's ability to minimize myocardial injury following an ischemic event may be, at least partly, mediated by its effects on the endothelium.

Many in vivo and ex vivo murine studies have shown both functional and structural benefits of exposing myocardium to quercetin in an acute ischemic setting — Table 1. These studies used rodent models in which transient myocardial injury was induced by ISO injections, surgical occlusion of the left coronary artery LAD or interruption of Langendorff perfusion , , , , — , — Quercetin was either given as an oral gavage, an intravenous or intraperitoneal infusion , , , , — , — Liu et al.

used echocardiography in mice to estimate left ventricular function They showed that quercetin significantly slowed the decline in LVEF and fractional shortening compared with the control group On macroscopic examination, treatment with quercetin induced a significant reduction of myocardial infarct size on triphenyl tetrazolium chloride TTC staining — This was further supported by lower levels of serum creatine kinase CK , CK-MB, cardiac troponin T and lactate dehydrogenase, all enzymatic markers of myocardial insult , — , — Histopathological examinations also revealed lower infiltration of leukocytes to the site of infarction, less edema and overall maintained tissue architecture , , All these findings are in favor of a preservation of cardiomyocytes' membrane integrity and global improvement in myocardial function after exposure with quercetin.

Interestingly, these cardioprotective effects were observed whether quercetin was administered before induction of ischemia or during reperfusion. This suggests that quercetin may have both ischemic preconditioning and postconditioning capacities.

As restoration of the circulation allows blood to reach cells that were previously subjected to ischemia, sudden availibility of oxygen leads to a burst in the generation of ROS, mainly deriving from the Fenton reaction, NOX, and xanthine oxidase XO These redox reactions lead to formation of oxygen radicals, lipid peroxidation, calcium overload, activation of inflammatory cascades, and apoptosis, which propagate and cause myocardial damage even distant to the original site of insult This has important clinical implications as it limits the benefits of current revascularization therapies such as thrombolysis, angioplasty or coronary artery bypass surgery A number of studies based on the rodent models of transient myocardial infarction have suggested that quercetin attenuates MIRI by interfering with several of these pathways Figure 4.

Figure 4. Schematic representation of the multistep mechanisms of quercetin to mitigate myocardial ischemic reperfusion injury. XO, xanthine oxidase; NOX, NADPH oxidase.

First, quercetin has well-documented antioxidant properties. Thanks to its chemical structure Figure 2 , it is able to directly scavenge free radicals such as superoxide, hydrogen peroxide, peroxyl, and hydroxyl radicals Quercetin can also reduce the formation of ROS by inhibiting NOX and XO, decreasing the activity of cyclooxygenase and LOX, as well as regulating the activity of intracellular signaling cascades involved in inflammatory reactions Chemical studies revealed that quercetin can reversibly inhibit XO-catalyzed uric acid and superoxide radicals formation in a double-displacement reaction , However, results of in vivo studies remain controversial In a rabbit model of surgically-induced MIRI, an intravenous injection of quercetin given 5 min before ligation attenuated the enzymatic activity of NOX2 expressed in endothelial cells On the other hand, quercetin acts as a chelating agent.

It can inhibit the Fenton reaction by interfering with ferrous iron It can also bind to zinc and facilitate zinc trafficking into cells , which in turn functions as an antioxidant Lipid peroxidation is the process by which unsaturated fatty acids are converted to lipid peroxyl radicals by hydrogen oxidation, which, in turn, extract hydrogen from other fatty acid molecules to create more free radicals Some studies reported that quercetin offers a protection against lipid peroxidation chain reaction by neutralizing peroxyl radicals and by binding to transition metal ions, catalyzers of lipid peroxidation , , Finally, quercetin pretreatment was shown to decrease the content of malondialdehyde MDA , a mutagenic product of lipid peroxidation chain reaction, and to potentiate the activity of superoxide dismutase SOD and glutathione peroxidase GSH-Px , two most important antioxidases in cardiomyocytes , , , , , All these properties allow quercetin to slow down the domino effects of free radical injury in MIRI.

With myocardial ischemia and MIRI, there is a shift toward a pro-inflammatory and pro-apoptotic phenotype caused by an increased secretion of cytokines As seen previously, quercetin was shown to significantly repress this inflammatory cascade, both in vivo and in vitro The pro-inflammatory response is further exacerbated by activation of NFκB, which is a pivot transcription factor in promoting cytokine expression.

Enhanced NFκB signaling induces a positive feedback, which further prompts inflammasome assembly NFκB can be activated through the interaction of high mobility group box-1 HMGB1 with toll-like receptors TLRs located in cardiomyocytes HMGB1 has been found to be released by necrotic cardiomyocytes under ischemic conditions and may serve as an early mediator of inflammation following MIRI Treatment with quercetin significantly inhibited expression of HMGB1 and TLR4 , In addition, up-regulation by quercetin of peroxisome proliferation-activated receptor gamma PPAR-γ further supports the targetting of NFκB activation Several reports revealed that PPAR-γ, a ligand-activated nuclear transcription factor, could suppress the signal transduction of NFκB pathway in vascular diseases A study demonstrated that mice with transient LAD ligation that received a 10 day pre-treatment of quercetin had a significantly higher number of PPAR-γ positive myocardial cells The authors also found that quercetin partially reversed the effects of a PPAR-γ inhibitor, GW, compared to non-quercetin-treated mice, with an associated improvement in LVEF, fractional shortening and cardiac biomarkers Lastly, quercetin was shown to protect against calcium overload.

Increased calpain activity has been reported as an aggravating factor in myocardial infarction This cardioprotective effect was also supported by a reduction of CK-MB and cardiac troponin T in quercetin-treated rats compared to the control group Another in vivo study found that quercetin prevented inhibition of the sodium-potassium and the calcium pumps caused by myocardial infarction Despite extensive experimental data suggesting that quercetin can attenuate MIRI, very few trials have explored the use of quercetin for the treatment of myocardial ischemia in humans.

In the study done by Chekalina et al. The quercetin patients had lower levels of IL-1β and TNF-α compared to the control group An open-label clinical trial conducted in Ukraine studied the administration of intravenous quercetin Corvitin over 10 days in patient admitted with an acute myocardial infarction and heart failure symptoms.

After 3 days, there was a significant improvement in their profile of cardiac biomarkers and LVEF Altogether, these clinical data suggest that quercetin has potential cardioprotective effects, and form a solid foundation for a potential application of quercetin in the prevention of IHD and its complications.

This hypothesis remains to be tested in large clinical trials. In the late 's, endothelial cells were found to undergo a highly dynamic process of dedifferentiation known as endothelial-to-mesenchymal transition EndoMT During EndoMT, endothelial cells progressively acquire a wide spectrum of phenotypes characteristic of multipotent cells Similar to senescence, EndoMT is a double-edged sword.

EndoMT-derived cells exhibit hallmarks of invasive cells through cytoskeletal reorganization, increased ECM production, loss of cellular adhesion and resultant enhanced migratory potential , This process is critical in the developing embryo where it was shown to generate vasculogenesis and the cardiac cushions for valve development EndoMT was also shown to contribute to wound healing However, when triggered under certain pathological conditions such as inflammation or shear-stress injuries, EndoMT can give rise to cancer progression , fibrodysplasia ossificans progressive , pulmonary arterial hypertension , or cardiac and renal fibrosis , The best-studied mediator of EndoMT is TGF-β The latter can induce EndoMT either directly, through both Smad -dependent and Smad -independent pathways , , or indirectly, through ET-1 , , CAV-1 , or NFκB , , Strong lines of evidence support the cross-links between endothelial dysfunction, atherosclerosis, hypertension, senescence and EndoMT , — Targeting EndoMT opens therefore a new therapeutic avenue against CVD.

However, contrarily to the other players of endothelial dysfunction, few studies specifically looked at the potential contribution of quercetin. In their study performed in vitro , Huang et al.

showed that quercetin effectively inhibited TGF-β1-induced human pulmonary arterial endothelial cells proliferation and transdifferentiation This suggests that quercetin may be a potential antagonist for a pathogenic model of pulmonary artery hypertension secondary to pulmonary arterial endothelial cells excessive growth.

Moreover, as discussed in previous sections, experiments done outside the scope of EndoMT have demonstrated that quercetin can downregulate ET-1 , , CAV-1 , and NFκB, which are all mediators of EndoMT.

In human retinal pigment epithelial cells ARPE exposed to TGF-β1, quercetin suppressed proliferation, migration, and collagen I secretion It also downregulated EMT-related markers such as alpha-smooth muscle actin and N-cadherin; conversely, it upregulated the expression of tight junction proteins and epithelial-cadherin Incubation with quercetin also reduced EMT in mammary carcinoma and prostate cancer cell lines , Together, these results support a role for quercetin against EndoMT and EMT.

However, despite multiple similarities between the two processes, including canonical TGF-β signaling as their driving force , more research in EndoMT models is needed to further confirm the efficacy of quercetin in targeting its trigger mechanisms.

The magnitude of the role of endothelial dysfunction in CVD is well-established. Many pathophysiological processes are involved, and they contribute to each other in a feedback manner, as seen with the triad of vascular senescence, hypertension and atherosclerosis.

This also means that each pathway is a potential target for alleviating endothelial dysfunction. Numerous drugs are already available to effectively treat dyslipidemia and hypertension.

In comparison, anti-senescence therapy is only a nascent yet promising research field. Development of senolytic drugs would bring a conceptual change that an aging vessel is not an immutable process. On the other hand, an important clinical consequence of endothelial dysfunction is manifested in IHD.

The burden of myocardial ischemia has been improved with more timely and effective reperfusion strategies such as angioplasty, bypass surgery, antiplatelet, and antithrombotic agents used to restore the patency of infarct-related coronary arteries. However, at present, there is still no effective therapy to prevent MIRI.

In this review, we have described mechanistic, experimental and clinical evidence that suggests quercetin can manifest a wide range of cardioprotective biological activities Table 1. Not only does it have anti-hypertensive and anti-atherosclerotic effects, but it also seems to mitigate senescence and MIRI, two Achilles' heels in the modern treatment of CVD.

Moreover, although still scarce, encouraging data suggest that quercetin may also act against abnormal EndoMT, an important yet less explored player in endothelial dysfunction. These properties of quercetin form the basis for its potential benefits against aging-related endothelial dysfunction and CVD Figure 5.

Figure 5. Schematic representation of the endothelial and, by extension, myocardial protective effects of quercetin. These allow quercetin to act as a primary, secondary and tertiary preventive measure against cardiovascular diseases.

While this review has focused on conditions originating from a diseased endothelial layer, prevention of endothelial dysfunction can be achieved by intervening beyond the endothelium itself. Indeed, endothelial dysfunction is undeniably associated with the remaining entities of the metabolic syndrome: obesity and insulin resistance — Their role as independent risk factors for CVD merits as much attention as hypertension and dyslipidemia In fact, the increasing incidence of obesity and corresponding rise in type-2 diabetes are further challenging the prevention and treatment of CVD The metabolic effects of quercetin against these two conditions have been equally encouraging and were recently reviewed elsewhere — In addition, it should be emphasized that, for clarity reasons, the effects of quercetin on the various biochemical and biomechanical signaling cascades involved in endothelial dysfunction were discussed as separate entities.

However, in reality, senescence, vasomotor dysfunction, atherosclerosis, EndoMT, inflammation, oxidative stress, and altered endothelial cellular metabolism all interact, cross talk and occur simultaneously. The resulting chain reactions create a vicious circle, which, once it is established in one person, can easily multiply their cardiovascular risks.

The ability of quercetin to act as such a versatile multi-target agent against the domino effect of endothelial dysfunction becomes very appealing. It seems to be promising not only in primary prevention, but also in secondary and tertiary prevention against the dysfunctional coronary endothelium and myocardium exposed to ischemia-reperfusion injuries.

However, after being studied for two decades and showing encouraging in vitro and in vivo results, quercetin still occupies a modest title as a dietary supplement.

This could be explained by a couple of factors. First, quercetin lacks molecular specificity. It does not radically block a metabolic pathway nor inhibit a receptor of interest. Instead, quercetin has a wide variety of biological activities, which makes it difficult to establish a clear association between its administration and the observed positive effects.

As a matter of fact, quercetin's role as a direct senolytic agent is still open for discussion. Does it selectively target SCs, or does it improve their clearance by off-target mechanisms such as antioxidant activity? Second, clinical trials using more consistent protocols are needed to consolidate the medical findings attributed to quercetin.

Published trials have been using various treatment durations, doses and routes of administration, certainly contributing to heterogenous findings. The considerable variation in bioavailability of quercetin among individuals might result in subtherapeutic plasma concentrations, especially when using lower doses.

Furthermore, in vitro experiments most often administered a hit-and-run treatment with quercetin. We could hypothesize that replicating this regimen in humans would yield more substantial effects. If a defect of the endothelium was accountable for a disease, and a drug could be given which would correct the defect, the disease would obviously be cured.

However, drugs that were to act through less direct principles might still be useful. For example, if quercetin's well-established anti-inflammatory and antioxidant effects, albeit less specific, could make the endothelium less vulnerable to injury and senescence, it could potentially reinforce the efficacy of other cardiovascular agents.

In conclusion, quercetin represents a promising natural compound that appears to satisfy all the requirements to develop a nutraceutical against endothelial dysfunction. There is a pressing need for well-designed clinical trials that explore its intriguing potential for senolytic therapy and myocardial protection.

OD, NT-T, and ET designed the project and its main conceptual ideas. OD performed the research strategy, data collection, data analysis and interpretation, drafted the manuscript, and designed the figures, with input from all authors.

All authors provided critical revisions to the article and approved the final version for publication. This work was supported by the Canadian Institutes of Health Research [PJT and PJT to ET]; and the Foundation of the Montreal Heart Institute [ET and MC].

PM is a post-doctoral scholar from the Fonds de la recherche du Québec. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Purchase PDF. Graphical Abstract. Mark Item. Current Topics in Medicinal Chemistry. Title: Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin Volume: 15 Issue: 17 Author s : Juan Guillermo Gormaz, Sebastian Quintremil and Ramon Rodrigo Affiliation: Keywords: Bioavailability , Cardiovascular diseases , Flavonols , Quercetin.

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Cite this article as: Gormaz Guillermo Juan, Quintremil Sebastian and Rodrigo Ramon, Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin, Current Topics in Medicinal Chemistry ; 15 Close About this journal.

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Nanopharmacology and Nanotoxicology: Clinical Implications and Methods. Article Metrics. Journal Information. Although quercetin can reduce systolic blood pressure in patients, it has no significant effects on other cardiovascular risk factors such as cholesterol, low density lipoprotein cholesterol LDL-C , triglycerides, TNF-α and IL-6 But the results of another randomized clinical trial were exactly the opposite.

The waist circumference, triacylglycerol and postprandial systolic blood pressure of healthy men with apolipoprotein E APOE genotype significantly decreased after oral administration of quercetin, while the level of TNF-α and high-density lipoprotein cholesterol HDL-C significantly increased Similarly, another study also found that although quercetin can reduce blood pressure, it has nothing to do with angiotensin converting enzyme ACE activity and ET-1 Therefore, the mechanism of quercetin in reducing hypertension still needs further in-depth research and exploration Table 5.

Heart failure HF is one of the serious CVD in clinical practice, and the main therapeutic drugs are β Receptor blockers, angiotensin converting enzyme inhibitors, or Ang II receptor antagonists.

HF is closely related to cardiac hypertrophy and oxidative stress caused by ROS. Many studies have confirmed that quercetin, a ROS scavenger, can improve redox balance and mitochondrial homeostasis by blocking H 2 O 2 and reversing mitochondrial Mn SOD activity, thereby reducing myocardial hypertrophy Tan et al.

In a mouse model of HF, quercetin promotes the de succinylation of isocitrate dehydrogenase IDH2 through SIRT5, maintains mitochondrial homeostasis, and improves myocardial fibrosis, thereby reducing the incidence of HF Although there are currently no human experimental studies on the correlation between quercetin and HF, we believe there will be breakthroughs in the near future Table 6.

Arrhythmias are a common disease with complex etiology in clinical practice. The inducing factors include changes in myocardial tissue, conduction bundle, intense exercise, drug stimulation, electrolyte disorders, and so on Arrhythmias have seriously affected the quality of life of the people.

Currently, the main methods for treating arrhythmia include radiofrequency ablation, artificial pacemakers, and drug therapy However, the current treatment of arrhythmia drugs and therapeutic efficacy are very limited. As one of the drugs that can effectively prevent and treat CVD, quercetin also has an important therapeutic effect on arrhythmia.

As a commonly used antineoplastic drug, doxorubicin mainly increases cardiac toxicity by increasing LDH, iNOS, and NO. In the doxorubicin induced myocardial injury model, quercetin can significantly reduce the incidence of arrhythmia by increasing SOD activity, inhibiting iNOS and myocardial cell apoptosis In addition, in the rat cardiomyopathy model, it was found that adding quercetin to drinking water can prevent the occurrence of lipid peroxidation in serum, thereby reducing arrhythmia It can be seen that quercetin has sufficient experimental evidence in the treatment and prevention of arrhythmia, and the road from laboratory to clinical is not far away.

Antiplatelet therapy, an essential tool in the arsenal against myocardial infarction MI or heart attack, remains a critical component of modern cardiovascular medicine Antiplatelet agents act as vital prophylactic and therapeutic measures by preventing the aggregation of platelets, crucial elements in clot formation and arterial blockage Furthermore, the potential of traditional Chinese medicine as an adjuvant treatment for MI is an emerging area of interest, with numerous studies investigating the therapeutic effects of various compounds and herbal formulations By combining conventional antiplatelet therapies with alternative treatments, to ultimately reduce the global burden of MI and improve patient outcomes.

In vitro studies have shown that quercetin can inhibit platelet aggregation by several mechanisms. Firstly, it can effectively inhibit platelet activators adenosine diphosphate ADP and TXA2, thereby reducing the release of platelet particles Zaragozá et al.

Perez et al. In a double-blind trial with 15 healthy volunteers, oral quercetin administration led to dose-dependent increases in quercetinO-glucuronide Q3GA levels. No blood pressure changes were observed, but quercetin-induced brachial artery diameter increases were found to correlate with Q3GA levels and plasma glucuronidase activity.

The study highlights quercetin's acute vasodilatory effects in individuals with normal blood pressure and cholesterol levels, consistent with Q3GA metabolite deconjugation.

In conclusion, quercetin has been shown to have antiplatelet effects in vitro and in vivo , by inhibiting platelet aggregation and thrombus formation through various mechanisms, including the inhibition of platelet granule release, integrin activation, and signaling pathways involved in platelet activation.

These effects suggest that quercetin may have potential as a natural supplement to complement antiplatelet therapy and reduce the risk of adverse side effects associated with these medications.

However, more clinical trials are needed to confirm these findings in humans and to determine the optimal dose and duration of quercetin supplementation. Further research is also needed to investigate the potential interactions between quercetin and antiplatelet medications, as well as the long-term effects of quercetin supplementation on cardiovascular outcomes.

CHD result from the narrowing or blockage of the coronary arteries responsible for supplying oxygen and nutrients to the heart muscle. This narrowing or blockage is primarily caused by the accumulation of plaque, consisting of cholesterol, fatty substances, and cellular waste products, within the arterial walls CHD can lead to various complications such as complication is angina, characterized by chest pain or discomfort due to inadequate blood flow to the heart muscle.

In more severe cases, CHD can result in myocardial infarction, heart failure, or even sudden cardiac death The pathophysiology of CHD involves a complex interplay of processes, such as endothelial dysfunction, inflammation, and oxidative stress Treatment for CHD typically involves a combination of lifestyle modifications, pharmacological interventions, and, in some cases, surgical procedures.

Additionally, the role of specific micronutrients and functional foods, such as omega-3 fatty acids, antioxidants, and plant-based compounds, is being investigated for their potential cardioprotective properties — Quercetin can inhibit the formation of CHD by attenuating oxidative stress and reducing the expression of adhesion molecules.

It also can promote the vitality, migration, and angiogenesis of human microvascular endothelial cells by downregulating the expression of intercellular cell adhesion molecule-1 and Vascular cell adhesion molecule-1, and inhibit cell apoptosis Abnormal lipid metabolism is one of the important risk factors for coronary heart disease.

Quercetin can also regulate lipid metabolism by regulating the expression of key enzymes involved in cholesterol synthesis, such as 3-hydroxymethyl glutaryl coenzyme A reductase HMG-CoA reductase, and is a new candidate drug for future development of cholesterol lowering drugs Although some studies have shown that quercetin has no impact on cardiovascular or thrombotic risk factors in healthy patients However, more research is needed to confirm the optimal dosage and duration of quercetin.

Furthermore, it is currently unclear whether there is a potential interaction between quercetin and existing cardiovascular drugs Table 6. Persistent hyperlipidemia can cause the recruitment of inflammatory cells and the production of ROS by damaging the vascular endothelial function, thus leading to a series of cardiovascular and cerebrovascular events such as atherosclerosis, arterial stenosis, thrombosis and stroke , — Although lipid-lowering therapy is the main treatment for hyperlipidemia, these drugs can also cause side effects and are not sufficient to completely lower blood lipids 21 , Therefore, people are increasingly interested in alternative and complementary therapies for hyperlipidemia, including the use of traditional Chinese medicine and functional foods Furthermore, it has been proven that quercetin can promote cholesterol efflux and promote the conversion of cholesterol into bile acids, thereby regulating liver cholesterol metabolism through these pathways.

Quercetin can also reduce the oxidation of low-density lipoprotein, thereby reducing the risk of developing hyperlipidemia Janisch et al. Gnoni et al. The decrease in de novo synthesis of fatty acids and triacylglycerol TAG induced by quercetin, subsequently leading to a reduction in the formation of VLDL, may represent a potential mechanism underlying quercetin's ability to lower triacylglycerol levels.

Despite promising results in vitro and in vivo studies, there are relatively few clinical trials of quercetin for the prevention or treatment of human hyperlipidemia.

A meta-analysis of five randomized controlled trials showed that quercetin did not significantly affect plasma LDL-C, HDL-C, and triglycerides During subgroup analysis, it was also found that only plasma triglyceride levels were significantly correlated with the dosage and supplementation time of quercetin.

Overall, the impact of quercetin on blood lipid levels is still uncertain, and its lipid-lowering effect may depend on the dosage and duration of supplementation. Flavonoids are the main bioactive components of quercetin, which have multiple functions such as antioxidant, anti-inflammatory, myocardial protection, lipid lowering, blood pressure lowering, and improvement of myocardial ischemia and arrhythmia.

However, the current research results on the mechanism and target of quercetin in the treatment of CVD are not uniform. The complex pharmacological actions and targets limit the application of quercetin in clinical patients. In addition, quercetin has the disadvantages of poor water solubility and low bioavailability.

In order to further increase the pharmacological effects of quercetin, many structural modifications have been made to quercetin, mainly including the modification of hydroxyl groups to generate ethers and esters, the modification of carbonyl groups to generate carbonyl oxygen substituted products, and the modification of quercetin A and B rings.

Quercetin derivatives with good solubility, high bioavailability, and significant biological activity were obtained through optimized modification 24 , Preparation of new dosage forms can also increase the pharmacological effects of quercetin, such as micro lotion, liposome encapsulation and nanocrystals.

In addition, the potential toxic side effects of quercetin may also be one of the reasons limiting its clinical application.

However, in fact, among numerous published human intervention studies, the adverse reactions after supplementation with quercetin have been rarely reported, and even the reported adverse reactions are very mild 3.

Although there are very few studies showing that prolonged and high-dose supplementation of quercetin can increase the risk of nephrotoxicity, it has not been found in human intervention experiments that quercetin increases nephrotoxicity in subjects with metabolic syndrome characteristics Overall, oral administration of quercetin in humans appears to be well tolerated, with only a very low incidence of adverse reactions observed so far.

However, this does not necessarily mean that quercetin has no toxic side effects, and more research is needed to confirm this. Although researchers have made significant contributions to improving the bioavailability of quercetin. Many in vitro and in vivo studies have shown that quercetin has the effect of treating and preventing CVD, but there are still few clinical trials of quercetin in CVD, especially heart failure, myocardial infarction, ischemia reperfusion, myocardial hypertrophy, myocarditis, and other diseases.

Even the doses and research results of quercetin used in clinical patients are uneven. In addition, it is not entirely clear which components of quercetin have practical applications, so it is necessary to further explore the monomer of traditional Chinese medicine.

It can be seen that quercetin still needs a long way to be truly used in the treatment of patients with CVD. Firstly, it is necessary to focus on how to further improve the water solubility and oral bioavailability of quercetin.

Secondly, the efficacy, mechanism of action, and unified application standards of quercetin in combination with other drugs. Finally, multicenter, large sample randomized controlled clinical trials are needed to further evaluate the safety and effectiveness of quercetin in CVD.

MD and YR conceived the topic and carried out manuscript editing. FY, WZ, and YZ drafted the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

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