Cardioprotective and Anti‐Hypertensive Effects of Epigallocatechin Gallate: Novel Insights Into Biological Evidence

ABSTRACT

Epigallocatechin gallate (EGCG), the major catechin in green tea, is of considerable interest principally due to its proposed antihypertensive and cardioprotective properties. New research shows that EGCG can help relax the circulation of blood vessels, reduce arterial stiffness of arteries, and promote antioxidant activity promotion, which results in lowering blood pressure (BP) and better‐improving heart health. It also affects signaling pathways related to nitric oxide (NO) production, inflammation, and oxidative stress, which are crucial for vascular homeostasis. Although animal research and clinical trials demonstrate that regular intake of EGCG significantly decreases BP and improves lipid profiles, further studies are needed to confirm these benefits in diverse populations. This review highlights the relevant biological data supporting these effects and the mechanisms by which EGCG impacts cardiovascular health. This review provides a new perspective on the many favorable effects of EGCG, such as its potential role in cardiovascular disease prevention, essential hypertension (HTN), and atherosclerosis. These results point to the need for more clinical trials aimed at determining whether EGCG may be used as a natural approach to reducing HTN and its cardiovascular complications through dietary interventions to enhance public health.

Abbreviations

BP

blood pressure

EGCG

epigallocatechin gallate

HTN

hypertension

MAP

mean arterial pressure

MI

myocardial infarction

NO

nitric oxide

NOS

nitric oxide synthase

1. Introduction

Hypertension (HTN), often termed the “silent killer,” is a significant risk factor for cardiovascular diseases, which remain one of the leading causes of morbidity and mortality worldwide [1]. As the global prevalence of HTN continues to rise [2], there is growing interest in dietary and lifestyle interventions that may provide effective management and prevention strategies. Among these, epigallocatechin gallate (EGCG), a major catechin found in green tea, has emerged as a promising candidate due to its potential anti‐hypertensive and cardioprotective effects [2, 3, 4].

Numerous studies have highlighted EGCG's ability to modulate various physiological processes that contribute to cardiovascular health. Its antioxidant properties help combat oxidative stress, a key player in endothelial dysfunction and vascular inflammation [5, 6]. Additionally, EGCG has been shown to improve endothelial function, reduce arterial stiffness, and influence signaling pathways that regulate blood pressure (BP). These mechanisms suggest that EGCG could serve as a natural therapeutic agent for managing HTN and promoting heart health [5, 6, 7, 8].

This review seeks to consolidate current biological evidence supporting EGCG's antihypertensive and cardioprotective properties. It aims to provide new insights into EGCG's potential as a dietary intervention for HTN and cardiovascular disease prevention by clarifying its mechanisms of action and reviewing pertinent clinical and preclinical studies. Finally, studying EGCG's therapeutic properties may contribute to the development of effective natural strategies for regulating cardiovascular health.

2. Method

A comprehensive literature review was conducted to discover studies on EGCG. The searches were done from January 2000 to October 2024 using PubMed, Scopus, Web of Science, and Google Scholar. The search strategy used was (“Epigallocatechin gallate” OR “EGCG” OR “green tea”) AND (“hypertension” OR “blood pressure”) AND (“cardiovascular health” OR “heart disease” OR “vascular function”). Filters were used to combine English peer‐reviewed studies with clinical, preclinical, in vitro, and in vivo studies. Only articles with specific inclusion criteria were selected, such as RCTs, observational and clinical studies, and animal studies that investigated the effects of EGCG on cardiovascular parameters such as BP, endothelial function, and lipid metabolism. Only articles that complied with the above criteria and reported quantitative and qualitative cardiovascular outcomes were considered. Non‐peer‐reviewed articles, studies without a cardiovascular focus, and studies with unclear methodology and outcome measures were excluded.

The study selection process had three steps. Two authors, A.B. and R.E., independently examined the titles and abstracts to identify potentially relevant articles. The full‐text articles were then reviewed to determine relevancy and fulfill the inclusion criteria. The discrepancies were resolved through consensus or with the assistance of a third reviewer, M.P. The PRISMA flow diagram included information on the number of records identified, screened, and excluded.

The reviewers used a standardized form to extract data that was independent of them and included study characteristics such as author and year, population, intervention, dosage details, and results. Key outcomes included changes in BP, endothelial function, and lipid profiles. A narrative synthesis was used to compare the extracted data.

The results were given in tables summarizing study characteristics and findings, with additional figures depicting patterns in EGCG's cardiovascular effects. There was also a narrative synthesis that explained the trends and potential clinical applications of EGCG in cardiovascular health management.

3. EGCG

EGCG, a potent polyphenol primarily found in green tea, has shown significant therapeutic potential across various diseases due to its antioxidant, anti‐inflammatory, and anti‐carcinogenic properties [9, 10].

Green tea polyphenols have been shown to extend the lifespan of mice, flies, and nematodes [11, 12]. EGCG has neuroprotective effects [13, 14] and can prevent the progression of many types of tumors, such as endometrial adenocarcinoma, hepatocellular carcinoma, and lung cancer [15, 16, 17]. EGCG is beneficial in assuaging P. gingivalis‐induced periodontitis due to its anti‐inflammatory effects [18]. Treatment with EGCG can improve endothelial function [19], lower triglycerides (TGs), total cholesterol (TC), low‐density, and very low‐density lipoprotein cholesterol (LDL‐C) fractions, and increase high‐density lipoprotein cholesterol (HDL‐C) and leptin [20, 21]. For heart failure with diastolic failure and preserved systolic function, ECGC is of important interest [22]. It has been revealed that it can also decrease the size of myocardial infarctions (MI) and enhance the ultrastructure of cardiomyocytes [23].

4. EGCG and Its Effects on Various Pathologies

It has been shown to have promising effects in the treatment and prevention of non‐communicable chronic diseases [24], enhancing BP modulation [25] and decreasing the risk of diabetes [26]. Furthermore, EGCG improves lipid profile and blood glucose and has antioxidant, anti‐inflammatory [27], anti‐carcinogenic [9], and anti‐atherosclerotic effects [28]. EGCG attenuates the level of TGs [29], cholesterol, LDL [24], and free fatty acids concentrations [30]. It may also decline lipid absorption from the intestine, which is associated with improved liver TG concentrations and insulin resistance [31]. EGCG improves oxidative stress [32] and increases lipid oxidation [33], which are key obesity‐related factors. It controls appetite by modulating hormones [34] or delaying gastric chymus emptying [34]. Thus, EGCG may reduce body weight and pertinent diseases [35, 36].

EGCG affects stress [37]. It can attenuate corticosterone levels to provide hypnotic and anxiolytic effects [38]. It decreases anxiogenic behavior, improves the quality of sleep [39], and increases sleep time without any specific side effects [40]. In patients with MS, where the interleukin 6 (IL‐6) level is high, EGCG attenuates the levels of IL‐6 and improves anxiety and functional capacity [41]. Additionally, it reduces the risk of CVDs in patients with MS [41]. It has been demonstrated that EGCG has neuroprotective effects that decrease the severity of autoimmune encephalomyelitis by attenuating demyelination and brain inflammation damage [42].

The modulatory activity of EGCG on connective tissues has been widely investigated. It has been studied that EGCG has the ability to treat unexplained infertility and shrink uterine fibroids as one of the major causes of idiopathic infertility [43]. Moreover, EGCG has beneficial effects on bone‐related metabolic and differentiation processes [44]. EGCG can improve the healing of femoral bone defects [51] and is demonstrated to regulate the activities of several cells, which promotes the healing of bone fractures [45]. EGCG promotes wound healing because of its antioxidant, anti‐inflammatory, and antiangiogenic properties. It decreases scare thickness and positively affects elasticity, hydration, and erythema; thus, it can be useful in scare management [46]. In addition, EGCG solution, as prophylactic skin care, significantly decreases the severity and incidence of radiation‐induced dermatitis [47].

The potentialities of EGCG in various conditions have been widely studied. It enhances the efficacy of epidural catheter analgesia management in patients with multiple rib fractures [48] and some drugs, such as nintedanib [49], Lisinopril [50], and fexofenadine [51]. EGCG has also been demonstrated to inhibit the development and metastasis of different cancers, such as colon and prostate malignancies [52, 53, 54].

5. EGCG and HTN: Mechanisms of Actions

Typically, HTN arises from a combination of multiple factors, including environmental factors and genetic predisposition [55]. The conventional pathophysiology of HTN involves increased sympathetic nervous system activity, triggering the activation of the renin‐angiotensin‐aldosterone system, vascular endothelial dysfunction, insulin resistance, and the dysregulation of neurohormonal factors [56, 57]. Regrettably, even with the ongoing advancement of antihypertensive medications and the emergence of novel surgical techniques, effectively managing HTN remains considerably unsatisfactory [58]. This issue could be attributed, at least in part, to the current drugs not adequately targeting the relevant mechanisms and the counter‐regulatory responses triggered by these treatments, leading to a reduction in their ability to lower BP. As a result, there is a pressing need for innovative treatment approaches [57].

The renin‐angiotensin system (RAS) regulates the balance of sodium and BP by employing coordinated mechanisms within the central nervous system (CNS), kidney, and cardiovascular system [59, 60]. This system's effects are brought about by the conversion of angiotensinogen into angiotensin I through the action of renin, followed by the angiotensin‐converting enzyme (ACE) cleaving angiotensin I to produce angiotensin II (Ang II). As the ultimate effector of this system, Ang II activates angiotensin II type 1 receptors (AT1R) found in the CNS, kidneys, and blood vessels, leading to an increase in sympathetic activity, reabsorption of the sodium, and vasoconstriction [59].

EGCG exhibits mighty antioxidant and anti‐inflammatory properties, making it a recommended supplement for cardiac health. Studies have demonstrated that the molecules extracted from green tea have BP‐lowering effects, including lowered systolic BP and diastolic BP, −1.17 and −1.24 mm Hg [61]. In vivo, investigations have shown that the impact of EGCG on decreasing BP by 8.7% depends on both the duration and dosage of administration beyond 2 weeks [62] and almost reduced mean BP by about 8%–10% [63]. Preliminary research suggests that EGCG may act as a potential blocker by suppressing the activities of renin and ACE in both in vitro and in silico studies [64, 65]. In a 2022 study, EGCG progressively repressed the increase of systolic BP by ‐23, −17, −13, and −11 mmHg (reductions of 11.6%, 8.7%, 6.7%, and 5.9%) following 4, 3, 2, and 1 weeks of supplementation. These impressions on reducing BP were crucially correlated with intrarenal alterations in the Agtr2, Ace, and Ren transcriptional levels [3].

The pathophysiology of essential HTN goes beyond a simple increase in BP; it involves an accurate equilibrium between vasoconstrictors and vasodilators, which play a crucial role in this condition [66].  Disruption of this balance contributes to endothelial dysfunction, causing an extreme release of substances that have vasoconstrictive properties [66, 67, 68]. Another significant factor in the development of EH is the heightened stress of oxidation and changes in the total antioxidant capacity (TAC), commonly observed in various CVDs [69, 70, 71, 72, 73].

In recent years, it has become evident that oxidative stress plays a role in high BP by causing inflammation, kidney dysfunction, and vascular constriction [74]. It has been demonstrated that mitochondria, a notable origin of O2·− radicals, experience impaired functioning in HTN, illustrating its novel role in this disease [75, 76]. Research has shown that HTN and endothelial dysfunction are linked to the molecular process in which the dysfunction of mitochondrial deacetylase Sirtuin (Sirt)3 leads to hyperacetylation and so inactivation of SOD2, a pivotal antioxidant found in mitochondria [77]. Investigations on human and animal models with EH have revealed a significant reduction in Sirt3 expression and activity in association with HTN [77].

EGCG has been shown to have potent anti‐inflammatory and antioxidant features, making it useful for cardiovascular health [78]. The polyphenols found in green tea act as scavengers for reactive oxygen species (ROS), producing phenolic radicals that are more stable [79]. The potential of EGCG to scavenge radicals has been extensively studied, primarily due to its high concentration in green tea and the D and B ring containing galloyl group [79]. Through electron paramagnetic resonance (EPR) spectroscopy, it has been observed that EGCG interacts with O^2–, resulting in the D‐ring oxidation [80]. Additionally, EPR studies have indicated that EGCG can also scavenge O^2– and OH [81]. Alvarez‐Cilleros et al. have indicated that EGCG can prevent dysfunction of the endothelium in human umbilical vein endothelial cells (HUVECs) by reducing the generation of ROS and inhibiting stress‐related pathways [82].

Nitric oxide (NO) production via the endothelial isoform of nitric oxide synthase (eNOS) in the endothelial cells (ECs) plays a pivotal role in regulating vascular tone and systemic hemodynamic [83]. When NO reaches vascular smooth muscle (VSM), it facilitates the production of cyclic guanylate monophosphate (cGMP) through guanylate cyclase [84, 85]. Consequently, cGMP provokes smooth muscle relaxation and governs inflammation and cellular proliferation within the vessel wall [86]. To elaborate, diffusion of NO through the vascular smooth muscle cells (VSMCs) became a stimulant for activating the cGMP‐ protein kinase G (PKG) axis. This activation, in turn, triggers Ca2+‐activated potassium channels, leading to hyperpolarization of the membrane and inhibition of Ca2+ influx extracellularly and/or release of Ca2+ from the endoplasmic reticulum, ultimately causing vasodilation. Additionally, activation of the PKG reduces VSMC contractility by phosphorylation of myosin light chain phosphatase (MLCP) [87, 88]

EGCG exhibits various effects, including the modulation of Ca²⁺ channels and the reduction of ROS generation almost about 26%–30% [89]. Interestingly, studies conducted by Campos‐Toimil et al. in 2007 demonstrated that EGCG‐induced relaxation may have a biphasic nature. Initially, EGCG was found to trigger an influx of Ca2+ into smooth muscle cells of the aorta in rats through nonselective cation channels with Ca2+ permeability and voltage‐operated Ca²⁺ channels. EGCG's primary mode of action involves activating the phosphatidylinositol 3‐kinase (PI3K)‐Akt‐NO/cGMP pathway [90]. Additionally, EGCG inhibits PDE activity, leading to increased cyclic nucleotide levels of approximately 33%–88% [91]. In a study in 2022, it was demonstrated that EGCG therapy ameliorates endothelial dysfunction. The researchers hypothesized that EGCG treatment may elevate plasma NO levels, contributing to the detected rise in endothelium‐dependent relaxation in response to acetylcholine. This resulted in BP declining approximately 40% in comparison with angiotensin II‐infused hypertensive mice with no treatment [8]. However, among Male non‐smokers, 40–65 years old, with 28< BMI <38, EGCG decreased diastolic BP (mean change: placebo −0.058 vs. EGCG −2.68  mmHg) [92], and another randomized clinical trial by Wilasrusmee et al. discovered that EGCG can reduce SBP, DBP, and mean arterial pressure (MAP) by about 120.93–115.5, 81.87–77.85, and 94.89–90.57 mmHg, respectively [93].

Figure 1 demonstrates how EGCG decreases the risk of atherosclerosis by prohibiting Notch receptor activity induced by oxidized LDL. EGCG can decrease the ROS level in mitochondria and stabilize the potential of the mitochondrial membrane, therefore attenuating cell swelling and endothelial cell apoptosis. EGCG and catechin can increase the eNOS, preserving endothelial function. EGCG can limit oxidative stress by regulating the p38 MAPK and ERK1/2 pathways. The main mechanism involves the activation of PI3K by EGCG through a yet‐to‐be‐identified receptor site localized on the cell membrane or in the cytoplasm, which stimulates the NO/cGMP signaling cascade and, in turn, elicits vasorelaxation.

FIGURE 1.

Protective mechanisms of Epigallocatechin‐3‐gallate (EGCG) against atherosclerosis through oxidative stress reduction and endothelial function preservation. Akt indicates α serine/threonine‐protein kinase; HO‐1, heme oxygenase‐1; NICD, Notch intracellular domain; Nrf, nuclear factor E2‐related factor; PI3K, phosphatidylinositol‐3‐kinase; TRPV, transient receptor potential vanilloid type.

6. EGCG and Other Vascular Diseases

6.1. Atherosclerosis

Atherosclerosis is a complex, chronic inflammatory condition affecting medium and large arteries driven by lipid accumulation. Key contributors to its progression include ECs, white blood cells, and smooth muscle cells within the artery walls. The most severe outcomes of atherosclerosis, like heart attack and stroke, result from the occurrence of additional blood clot formation [94]. Although atherosclerosis is typically associated with advancing age, it is noteworthy to mention that it is becoming more prevalent in younger individuals due to modern lifestyles. Nonetheless, it is commonly considered an ailment of the elderly [95]. Atherosclerosis follows a complex pathogenesis encompassing three significant factors: inflammation, lipid metabolism alteration, and endothelial lining damage [96].

Several studies have elucidated the potential benefits of EGCG, including anti‐inflammatory, antioxidant, and lipid‐lowering activities [25, 97]. Atherosclerosis‐related inflammation involves bioactive lipids, signaling pathways, proinflammatory cytokines, and adhesion molecules [98]. Signaling pathways such as NLRP3 inflammasome, Notch and Wnt signaling pathways, and toll‐like receptors are implicated in atherosclerosis development and regression [99]. Activation of Type II ECs through stress‐related stimuli like tumor necrosis factor‐α (TNF‐α) triggers the nuclear factor‐κB (NF‐κB) signaling pathway, a pivotal regulator of inflammatory responses [100]. In a study by Reddy et al., the inhibitory effect of EGCG on NF‐κB activation in ECs was investigated. HCAECs were stimulated with TNF‐α for an hour and treated with EGCG at the specific concentrations. The results showed that ECGG effectively suppressed NF‐κB transcriptional activity in TNF‐α stimulated HCAECs [100].

Furthermore, T cells secrete various inflammatory cytokines, significantly contributing to the progression of atherosclerosis. The impact of EGCG on cytokine production by human peripheral T cells was examined using a non‐toxic dosage range (0.1e20 mM) stimulation with P/I induced human T‐cell activation, EGCG dose‐dependently inhibited the production of INFg, TNF‐a, IL‐4, and IL‐2 in response to P/I stimulation [101]. Additionally, EGCG treatment was shown to reduce circulating levels of interferon‐γ monocyte chemoattractant protein‐1, interleukin‐6, and TNF‐α levels in apolipoprotein E‐deficient mice [102].

Altered lipid metabolism serves as a risk factor for the development and progression of atherosclerosis. Dyslipidemia plays a significant role in initiating atherosclerosis, where the accumulation of oxidized LDL triggers the disease onset. Oxidative stress on the Endothelium leads to the formation of oxidized cholesterol, named oxysterols. Both types of diabetes mellitus (DM) can induce or accelerate atherosclerosis development, with elevated glucose levels, dyslipidemia, and other metabolic changes closely implicated in atherosclerosis pathogenesis at various stages [103]. The Retention of LDL particles contributes to an increased risk of fatty streak development and atherosclerosis progression  [104]. Although lipid‐lowering therapies have been effective in treating atherosclerosis, CVDs remain the leading global cause of death [105].

In many studies, promising EGCG influences on lipid profile include reducing the levels of TC, TG, LDL‐C, and VLDL by approximately 75%–80%, 7%–8%, 10%–11%, and 6%–7%, respectively, and increasing the level of HDL‐C approximately about 50% with a high dose of EGCG in comparison with a model group during 10 weeks and diabetes indicators have been demonstrated [106, 107]. In a study by Niu et al., EGCG was found to potentially lower TC, TG, LDL‐C, and serum glucose (GLU) levels. In addition, it increased NO and HDL‐C levels, particularly during the later stage of the experiment [97]. In a study by Wang et al., EGCG administration was found to decrease atherosclerotic plaque formation in mice by increasing anti‐inflammatory cytokine and interleukin‐10 levels and reducing pro‐inflammatory cytokine, IL‐6 and TNF‐α levels. Furthermore, EGCG modulated high‐fat‐induced dyslipidemia, evidenced by reducing TC, TG, and LDL‐C levels by approximately 3%, 10%, and 2%–3%, respectively, and increasing HDL‐C levels by about 15% [102].

The endothelium is responsible for generating vasodilator (NO) and vasoconstrictor (endothelin) molecules. An imbalance in the production of these vasoactive substances results in the deterioration of endothelial function, known as endothelial dysfunction [27, 108]. The healthy functioning of the endothelium involves maintaining dynamic vascular tone, facilitating angiogenesis, regulating hemostasis, and serving as an antioxidant, anti‐inflammatory, and antithrombotic barrier. Vascular endothelial dysfunction manifests as compromised vasodilation, increased oxidative stress, chronic inflammation, elevated leukocyte adhesion and permeability, as well as endothelial cell aging  [109]. Initiated by endothelial injury, the accumulation and infiltration of the modified LDL particles within the subendothelial space transpire  [103].

Previous reports exhibited the protective feature of EGCG against CVDs through preserving endothelial function via anti‐inflammatory and anti‐oxidative influences, besides inducing NO production [110, 111]. Similarly, other studies showed that EGCG‐induced vasorelaxation primarily relies on a NO‐dependent mechanism, as evidenced by experiments involving the inhibition of endothelial NO production [112, 113, 114]. In a study by Kim et al. EGCG reduced intracellular lipid accumulation in aortic ECs by promoting the co‐localization of lipid droplets, LDs, and autolysosomes [115]. Furthermore, EGCG treatment showed promise in increasing fibrous cap thickness and reducing atherosclerotic lesions by about 25%, and also decreasing levels of TC, TG, and LDL‐C by approximately 50%, 30%, 30%–33%, respectively, and increasing the level of HDL‐C about 66%  [116]. Moreover, compared to the control group, the EGCG‐treated groups exhibited decreased expression levels of VEGFA and MMP‐2 in cardiac tissues, indicating a potential inhibitory effect of ECGC on atherosclerosis, including reducing the levels of TC, TG, LDL‐C, approximately 25%, 33%, 30% respectively, and increased the level of HDL‐C approximately about 50% with a high dose of EGCG in comparison with model group in mice with coronary heart disease [117].

6.2. Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a life‐threatening vascular disease. This disease is characterized by an irreversible localized dilation in the abdominal aorta; the aortic wall diameter is ≥3.0 cm or at least 50% greater than its normal diameter [118, 119].  Male sex, advanced age, tobacco use, obesity, genetic predisposition, older age, and family history are known as AAA risk factors [120, 121]. This disease affects 4%–8% of the male population over 65 years old, 4–6 times more than the female population. This dilation can exceed abruptly and end up in a ruptured AAA. Therefore, only 50% of these cases can make it to a medical center alive; among these patients, only 50% go through an emergent surgical repair [122, 123]. Rupture, as the most common vital consequence of aortic aneurysm, is in charge of 60% of the mortality rate [133]. In total, AAA annually results in 150 000–200 000 deaths globally and is considered a public health concern [123]. AAA pathophysiology is defined as a multifactorial process that consists of inflammatory responses, matrix metalloproteinase (MMP) activation, oxidative stress, intraluminal thrombus, smooth muscle apoptosis, and extracellular matrix (ECM) degeneration in the latest studies [124, 125, 126]. As a result, there is no FDA‐approved, safe, and effective medication available for this disease so far, and the only accepted management is an invasive endovascular intervention [127]. Preventive surgery is indicated in patients with an aortic wall diameter ≥5.5, asymptomatic patients with an AAA >4 cm that has grown >1 cm in 1 year, and symptomatic patients with any diameter [128]. Intervention is indicated when the risk of rupture takes over the risk of the surgery itself [123, 129], so a reliable treatment is needed for patients with aneurism that is not susceptible to rupture to decrease the aortic wall diameter rise or to decrease the risk of aortic aneurysm rupture [129, 130]. ECM degeneration is known as a mechanism that weakens the aorta wall and leads to aortic aneurysms [131]. The degeneration of elastin, one of the main ECM components in charge of vasodilation and rupture resistance in arteries, has a clarified role in aneurysm generation and progress [132]. Therefore, many studies have shown that it is a target for medications. In the following paragraph, we will look at some studies investigating the effect of Epigallocatechin on elastin degeneration and AAAs. Sinha et al. showed that polyphenols such as epigallocatechin have elastin regenerative effects on rat's primary aortic smooth muscle cells by investigating it in an in vitro environment. They reported that the group of cultured cells that were exposed to polyphenols gained more insoluble cross‐linked elastin in their structure [133]. Ellis and co‐workers reported that EGCG enhances elastin formation by increasing elastin gene expression and replicating mRNA half‐life in induced pluripotent stem cell‐derived VSMCs for tissue engineering [134]. Jin et al. published their study on the EGCG effect on stabilizing elastin fibers in pericardium cells in an in vitro environment, and they showed no broken elastic fibers in cells exposed to EGCG [135].

Setozaki et al. showed that EGCG intake can decrease the aorta's wall diameter in rats with abdominal aortic diameter induced by focal elastase injection in the aorta's wall. They compared two groups of rats. The intervention group took EGCG 2 weeks before the induction and continued for 2 weeks after induction. The aorta wall diameter was increased after induction in both groups, but in the intervention group, it was not as large as in the control group. However, it was almost smaller in the EGCG group, about 20%, in comparison with the control group (2.3 vs. 2.9 mm). The Intima layer was thinner in the intervention group, yet the media layer was thicker. Elastin composition was significantly higher in the intervention group before the intervention, and there was no noticeable difference in elastin decrease in both groups, but after the second day, elastin composition increased in the intervention group significantly. They reported that no adverse effect was detected in the intervention group, including no stenosis and no thickness in carotid arteries or coronary arteries [136]. This study was confirmed by David Tilson in a commentary letter. He reported that the results of their previous experiments and the Setozaki study support each other and are not controversial [137]. Another murine study was performed and reported in 2006 by Ro and colleagues; they reported significant differences in AAA dilation between two groups of rats that were/were not treated by AneuMastat. Furthermore, untreated mice had a significantly larger aorta diameter at sacrifice relative to their starting size (768 vs. 532 µm, p = 0.001). Additionally, no significant increase in aorta size was seen within treated or Sham mouses (550 vs. 580 µm and 478 vs. 477 µm). Aneumastat is a polyphenol‐rich EGCG that can be used as a preventive compound [138]. Another study by Tyrie et al. examined aneumastat as a preventive medication for AAA. They reported that although there was a significant decrease in the prevalence of AAA in mice taking aneumastat, AAAs (1.5× normal diameter) have been identified in 55% of the AngII group and 20% of the AngII AneuMastat(R) group. There was no histopathologic difference in aortic aneurysms between the two groups [139]. Since EGCG is one of the grape‐seed polyphenol (GSP) components, looking at the study that Ma et al. performed in 2020 is not out of grace. They examined the effect of GSP on AAA development. They demonstrated that GSP intake significantly inhibited AAA formation in male mice [140]. Another study was published 3 years ahead of Ma's study by Wang et al. which was quite similar. In this study, grape seed polyphenol administration also inhibited AAA development in rats [141].

6.3. Coronary Artery Disease (CAD)

CAD is a common heart condition recognized by stable angina, unstable angina, MI, or sudden cardiac death [142]. CAD develops due to plaque formation within the intima of the coronary artery walls. This occurs through the buildup of lipids and immune cells in the artery's subendothelium. The process triggers an inflammatory response in the vascular endothelium, leading to endothelial dysfunction, which is the primary driver of both atherosclerosis and CAD [143, 144–147].

The benefits of EGEC are categorized into three parts: Its effects on preventing and reversing endothelial dysfunction due to control plaque formation, its benefits on managing CAD‐related risk factors such as HTN, hyperlipidemia, or DM, and finally, its positive effects in treating patients with CAD [148, 149, 150].

Polyphenols such as EGCG enhance endothelial function and induce vascular relaxation, resulting in protective influences on the development and progression of CVDs [151]. Following MI, irreversible microscopic changes occur in the myocardium due to hypoxia [152, 153]. Although rapid reperfusion can help reverse the negative effect of hypoxia, several studies demonstrate that reperfusion could damage the myocardium through many pathways [154, 155, 156]. One of the main molecules involved in this process is ROS [155]. Other causes are immediate cellular PH correction and intracellular Ca⁺ increases [154]. Patients who have experienced acute myocardial ischemia and are candidates for reperfusion treatment might have some myocardial reperfusion injuries, such as cardiac dysfunction, an increase in myocardial infarct size, and cardiac fibrosis due to myocardial apoptosis.

It has been seen that the administration of EGCG in these patients reduces the reperfusion damage with different molecular pathways, of which the most important ones are tyrosine kinases and the SIRT1 signaling pathway in diabetic rats [157, 158]. In addition, in an experimental study on isoproterenol‐induced MI rats by Othman et al., EGCG exhibited a significant positive effect, especially if it was used as an early intervention in MI, by preserving redox balance and applying anti‐apoptotic character [26].

Myocardial apoptosis is a process that occurs in MI. Amongst numerous active molecules in apoptosis, P53 and bcl‐2 are shown to play a crucial role. The EGCG has an inhibitory effect on both of them; thereby, it has a positive influence against apoptosis. Thus, EGCG ameliorates cardiac hypertrophy, also the heart weight index (HWI) and left ventricular weight index (LVWI) were raised by 55.8% and 72.3%, respectively [159], and cardiac injury via reperfusion in MI in rats [159, 160]. Also, it has been demonstrated that EGCG positively affects the PI3K/Akt signaling pathway, leading to reduced ischemic reperfusion cardiac injury [161]. Furthermore, EGCG has a cardioprotective effect against reperfusion damage by inhibiting STAT‐1 activation [162]. EGCG positively impacts serum lipid profile as a major cardiovascular risk factor and improves the antioxidant system and myocardial fiber morphology to protect patients with a high hypercholesterolemia diet against hypercholesteremia‐related cardiovascular abnormalities [163]. Several studies suggest that EGCG is a complementary treatment in managing DM, another risk factor for cardiovascular disease by several molecular pathways [164, 165, 166], and EGCG exhibited protective effects against cardiovascular events in type 2 diabetes patients prone to CAD [26].

EGCG inhibits the development and progression of cancer by reducing angiogenesis, cell proliferation, invasion, and metastasis, enhancing apoptosis, and overcoming chemoresistance by regulating the activity of associated molecules. It also increases plasma and intracellular drug concentration and enhances drug efficacy.

7. Conclusions

Table 1 represents the cardioprotective potentials of EGCG reported by various studies. Figure 2 summarizes the effect of EGCG on cardiovascular health.

TABLE 1.

Cardioprotective potentials of EGCG reported by various studies.

Disease	Dose	Target (s)	Effect (s)	Model	Cell line/animal	Ref.
HTN	50, 250, 500 or 1000 mg/kg	Atgr2, Ace2, Agtr2, Ace, and Mas1 Ren mRNA	Activated the intrarenal counter‐regulatory axis (ACE/AngII/AT2R)	In vivo (animal)	Rat	[3]
	50 mg/kg	BH4, cGMP, eNOS, NOx‐2	Antioxidant effects	In vivo (animal)	C57BL/6J mice	[8]
	10 mg/kg	Oatp1a5, Oct1, P‐gp	Reduced nadolol bioavailability	In vivo (animal)	Rat	[167]
	1 mM	KCNQ5	Hyperpolarization of smooth muscle and vasodilation leading to mesenteric artery relaxation	In vitro (animal) in vivo (animal)	Stages V and VI Xenopus laevis oocytes Rat	[168]
	50 mg/kg/12 h	MDA, S100A4	Reduced urine volume, proteinuria, kidney fibrosis, oxidative, and inflammatory damage	In vivo (animal)	Dahl/SS rats	[169]
	300 mg/kg	miRNA‐126a‐3p, miRNA‐150‐5p, SP1, AT1R	Upregulated miRNAs, which are mainly involved in vascular smooth cell or endothelial cell apoptosis, proliferation, and migration, angiogenic pathways like MAPK and PI3K/Akt/eNOS	In vivo (animal)	SD rats	[170]
	200 mg/kg 1–100 µM	PI3K, NO, adiponectin	Stimulated endothelial production of NO, which is dependent on activation of PI3K, thus reduced BP. Enhanced the ability of insulin to mediate vasorelaxation Improved insulin sensitivity and adiponectin levels Mimicked vasodilator actions of insulin	In vivo (animal) in vitro (animal)	WKY, male SHR‐mesenteric vascular beds isolated from SHR	[171]
	50, 100 or 200 mg/kg/d	MFN‐2, KLF‐4/MFN‐2/p‐Erk1/2 signaling	Inhibited pulmonary artery smooth muscle cells Promoted mitochondrial fusion and inhibited proliferation	In vivo (animal)	Male SD rats	[172]
	20 mg/h.	NF‐kB, GAD67, IL‐1b and TH	Restored the balance between the excitatory and inhibitory neurotransmitters	In vivo (animal)	Male normotensive WKY rats	[173]
	458 mmol/L	PAH, TH, DBH, PNMT, SOD1, HDAC7, Noxa1	Altered epigenetic regulators antioxidant effect	In vivo (animal)	WKY rats	[174]
	50 µM	MAPK, MMP‐2, NF‐κB, Spm–Cer–S1P, SPHK, ERK1/2 SMase	Anti‐proliferative effects	In vitro (animal)	Bovine pulmonary artery smooth muscle cells	[175]
	2.5 µM, 75 mg/kg	HO‐1, p38 MAPK, Nrf‐2	Anti‐atherogenic effects	In vitro (human) in vivo (animal)	Human aortic endothelial cells, C57BL/6J mice	[176]
	10 µM	NF‐κB, TNF‐α, ICAM, VCAM, CCL2	Anti‐inflammatory effects	In vitro (human)	HCAECs	[100]
	300 mg/day	Kisspeptin, NO	Stimulated production of NO from endothelium Downregulated level of kisspeptin as a probable vasoactive substance	Human (clinical)	—	[25]
	800 mg/day	—	Anti‐hypertensive effects (reduced mean SBP: −2.85, DBP: −2.68 from baseline	Human (clinical)	—	[92]
	300 mg/day	—	Anti‐hypertensive effects (reduced approximately mean SBP: −4.2%, DBP: −4.9%, MAP: −4.5% from baseline	Human (clinical)	—	[93]
Cardiac hypertrophy	10–100 µM	ANP, BNP, IKKβ/NF‐κB signaling, ERKs, p38, JNKs, AP‐1, c‐Fos, c‐Jun	Blocked EGFR transactivation and its downstream events Attenuated NADPH oxidase	In vitro (animal) in vivo (animal)	Neonatal ventricular myocytes Male SD rats	[177]
	50 mg/kg	ANP, MDA, GPx, SOD, CAT, NF‐κB AP‐1, MMP‐9 MMP‐2	Attenuated pressure overload‐induced LV hypertrophy Antioxidant effect	In vivo (animal)	Male SD rats	[178]
Stroke	—	—	Delayed the stroke onset by 10% of the average lifespan Lowered the rate of increase in SBP and DBP Decreased nighttime and daytime HR	In vivo (animal)	Malignant Stroke‐prone spontaneously hypertensive rats	[179]
	10–50 µM	JNK signaling c‐jun mRNA	Inhibited Ang II‐stimulated VSMC hypertrophy	In vitro (animal)	Aortic smooth muscle cells of SD rats	[180]
Pre‐eclampsia	100 mg	—	Enhanced the efficacy of nifedipine in pregnancy‐mediated severe pre‐eclampsia patients	Human (clinical)	Pregnant women	[181]
AAA	20 mg/day (EGCG solution	TNF‐α, IL‐1β, MMP‐1, MMP‐9	Preserved the aortic thickness and elastin content of the medial layer via elastin regeneration Anti‐inflammatory effect	In vivo (animal)	Male rats	[136]
CaCl2‐induced AAA	250 mg/kg	Elastin, collagen fibrils	Prevented aortic aneurysmal dilation Anti‐inflammatory effect	In vivo (animal)	C57BL6 mice	[138]
AngII‐induced AAA	—	—	Reduced aortic aneurysm incidence	In vivo (animal)	C57BL6 mice	[139]

FIGURE 2.

Cardioprotective effects of EGCG on cardiovascular health.

In conclusion, EGCG possesses impressive anti‐hypertensive and cardioprotective properties encompassing a range of complex biological pathways. The level of research into its antioxidant capacity, ability to modify NO synthesis, and its role in inhibiting critical components of the renin‐angiotensin system are well documented. These actions increase vascular function, decrease oxidative stress, and lower BP. In addition to its BP‐lowering effects, EGCG has been demonstrated to suppress pathological changes in the heart, including cardiac hypertrophy, fibrosis, and inflammation, which are commonly observed in chronic HTN and cardiovascular diseases. The ability of this compound to target cellular signaling pathways associated with oxidative stress, inflammation, and fibrosis further supports its broad‐spectrum therapeutic activities. Although these positive preclinical and early clinical results are highly promising, further research is warranted to clarify the mechanisms of action and to evaluate the long‐term efficacy and safety of EGCG in humans, particularly in patients with HTN or other cardiovascular conditions. This emerging body of research points to the promise of natural compounds such as EGCG for developing novel therapeutic and preventive strategies for cardiovascular disease.

Author Contributions

M.H.P. developed the idea and supervised the project. R.E., A.B., F.T.I., M.K., M.S.S., M.H.P., M.Y., A.B., F.Q.T., J.S., F.H., and A.R. contributed to the primary drafting of the manuscript. M.K. reviewed and revised the manuscript. All authors critically read and approved the final manuscript.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

No new data were generated.