Gallic acid: a dietary metabolite's therapeutic potential in the management of atherosclerotic cardiovascular disease

Abstract

Atherosclerotic cardiovascular disease (ASCVD) causes significant morbidity and mortality globally. Most of the chemicals specifically target certain pathways and minimally impact other diseases associated with ASCVD. Moreover, interactions of these drugs can cause toxic reactions. Consequently, the exploration of multi-targeted and safe medications for treating and preventing ASCVD has become an increasingly popular trend. Gallic acid (GA), a natural secondary metabolite found in various fruits, plants, and nuts, has demonstrated potentials in preventing and treating ASCVD, in addition to its known antioxidant and anti-inflammatory effects. It alleviates the entire process of atherosclerosis (AS) by reducing oxidative stress, improving endothelial dysfunction, and inhibiting platelet activation and aggregation. Additionally, GA can treat ASCVD-related diseases, such as coronary heart disease (CHD) and cerebral ischemia. However, the pharmacological actions of GA in the prevention and treatment of ASCVD have not been comprehensively reviewed, which limits its clinical development. This review primarily summarizes the in vitro and in vivo pharmacological actions of GA on the related risk factors of ASCVD, AS, and ASCVD. Additionally, it provides a comprehensive overview of the toxicity, extraction, synthesis, pharmacokinetics, and pharmaceutics of GA,aimed to enhance understanding of its clinical applications and further research and development.

Keywords: ASCVD; atherosclerosis; cardio-vascular diseases; diabetes; gallic acid; hyperlipidemia; hypertension.

FIGURE 1

Molecular targets and mechanism of action of GA in hyperlipidemia. Green arrows and red arrows indicate promotion and inhibition, respectively. Description: This figure illustrates how GA regulates lipid metabolism in patients with hyperlipidemia. GA inhibits lipid synthesis by activating the AMPK pathway, downregulating SREBP-1c, SREBP-2, and ACCα. Simultaneously, it promotes fatty acid oxidation by decreasing PPARα expression and increasing ketone body levels. GA also reduces triglyceride accumulation by activating AMPKα, promoting autophagy, and inhibiting HSL and pancreatic lipase. Furthermore, GA suppresses inflammation by reducing TNF, CCL-2, and NOS levels, while enhancing mitochondrial function through UCP1, PGC-1α, and SIRT1. Additionally, GA induces adipocyte apoptosis by inhibiting the expression of Bcl-2 and Bcl-XL and promotes adipocyte differentiation, leading to increased production of adipokines such as adiponectin and Fabp4, thereby indirectly influencing lipid levels. These combined effects underscore GA’s potential for effective control of hyperlipidemia. Green arrows indicate promoting effects, while red arrows represent inhibitory actions.

FIGURE 2

Inhibition of atherosclerotic lesions by GA. Green arrows and red arrows indicate promotion and inhibition, respectively. Description: This figure illustrates how GA inhibits atherosclerotic lesions through multiple mechanisms. GA protects endothelial cells by increasing GSH levels and DNMT1 expression to reduce apoptosis, while improving mitochondrial function by inhibiting the ERK/CypD/NOX4 pathway. It also inhibits platelet activation and aggregation by suppressing thrombin activity, downregulating the PKC and p38/MAPK pathways, reducing Ca²⁺ influx, and decreasing P-selectin expression. Additionally, GA suppresses VSMC proliferation and migration by inhibiting the RhoA/CDC42 and PI3K-Akt-ERK1/2 pathways, while promoting VSMC apoptosis through the AMPK-eNOS-FAS pathway and mitigating oxidative stress caused by hydroxyl radicals (•OH). These effects collectively stabilize atherosclerotic plaques and prevent their progression. Green arrows indicate promotion, while red arrows represent inhibition.

FIGURE 3

GA inhibited the proliferation and migration of VSMCs. Green arrows and red arrows indicate promotion and inhibition, respectively. Description: This figure illustrates how GA inhibits VSMC proliferation and migration while inducing apoptosis. GA suppresses the RhoA/CDC42 and PI3K-Akt-ERK1/2 pathways, reduces the activation of NF-κB and Ras, and increases the expression of iNOS and KSR2. Additionally, GA promotes the AMPK-eNOS-FAS pathway, enhances Kip1/p27 and Cip1/p21 levels, and inhibits the expression of cyclin B1 and CDK1. Moreover, GA reduces hydroxyl radicals and alleviates oxidative stress to induce apoptosis. Green arrows indicate promoting effects, while red arrows represent inhibitory effects.

FIGURE 4

Molecular targets and mechanism of action of GA in T2DM. Green arrows and red arrows indicated promotion and inhibition, respectively. Description: This figure illustrates the molecular mechanisms by which GAexerts therapeutic effects in T2DM. GA enhances insulin secretion by inhibiting oxidative stress, apoptosis, and the formation of SFRP4. Simultaneously, GA improves insulin resistance by activating the PPARγ-PI3K/Akt-GLUT4 signaling pathway, thereby increasing glucose uptake. Additionally, GA delays glucose absorption by inhibiting the activities of SGLT1, GLUT2, and α-amylase. In the figure, green arrows indicate processes or pathways promoted by GA, while red arrows highlight inhibitory effects.