The Role of Anthocyanin in Modulating Diabetic Cardiovascular Disease and Its Potential to Be Developed as a Nutraceutical

Abstract

Cardiovascular disease (CVD) is directly linked to diabetes mellitus (DM), and its morbidity and mortality are rising at an alarming rate. Individuals with DM experience significantly worse clinical outcomes due to heart failure as a CVD consequence than non-diabetic patients. Hyperglycemia is the main culprit that triggers the activation of oxidative damage, inflammation, fibrosis, and apoptosis pathways that aggravate diabetic CVD progression. In recent years, the development of phytochemical-based nutraceutical products for diabetic treatment has risen due to their therapeutic properties. Anthocyanin, which can be found in various types of plants, has been proposed for preventing and treating various diseases, and has elicited excellent antioxidative, anti-inflammation, anti-fibrosis, and anti-apoptosis effects. In preclinical and clinical studies, plants rich in anthocyanin have been reported to attenuate diabetic CVD. Therefore, the development of anthocyanin as a nutraceutical in managing diabetic CVD is in demand. In this review, we unveil the role of anthocyanin in modulating diabetic CVD, and its potential to be developed as a nutraceutical for a therapeutic strategy in managing CVD associated with DM.

Keywords: apoptosis; cardiac dysfunction; cyanidin; delphinidin; diabetic cardiomyopathy; fibrosis; inflammation; oxidative stress; vascular dysfunction.

Figure 1

The illustrated mechanisms propose the pathogenesis of diabetic CVD. Hyperglycemia is the main culprit that induces and enhances the activation of fatty acid metabolism and nonoxidative glucose pathways, AGEs, polyol, hexosamine, and PKC pathways, which cause high generation of ROS. ROS causes downregulation of Nrf2, which reduces the activity and level of endogenous antioxidants, which ultimately causes oxidative stress. ROS also triggers the activation of NF-κB and raises the inflammasome, NLRP3, and inflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1, ICAM-1, VCAM-1), which leads to inflammation. The inflammatory response upregulates TGF-β and triggers the profibrotic response, as well as CTGF, which further causes ECM accumulation, collagen deposition, and, in the end, fibrosis. ROS causes mitochondrial dysfunction and further enhances oxidative stress. Mitochondrial dysfunction and oxidative stress triggers the cascade of apoptosis by activating apoptosomes and caspases. These mechanisms ultimately cause cardiac hypertrophy, cardiac fibrosis, endothelial dysfunction, vascular stiffness, myocardial ischemia, and ultimately, diabetic CVD. Abbreviations: AGE, advanced glycation end product; PKC, protein kinase C; ROS, reactive oxygen species; Nrf2, nuclear factor erythroid 2-related factor 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NLR family pyrin domain containing 3; TNF-α, tumor necrosis factor alpha; IL, Interleukin; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion protein 1; CTGF, connective tissue growth factor; ECM, extracellular matrix; TGF-β, transforming growth factor beta ; Apaf-1, apoptotic protease activating factor 1. Arrow represent the subsequent event/product in the pathway.

Figure 2

The chemical structure of subtypes of anthocyanin.

Figure 3

The summary of the role of anthocyanin in attenuating mechanisms of diabetic CVD. Anthocyanin increases NO bioactivity and upregulation of Nrf2, which induces the production of endogenous antioxidants and limits oxidative stress. Anthocyanin also has been proposed to downregulate NF-κB and lead to reduced expression and production of cytokines involved (TNF-α, IL-1β, IL-6, ICAM-1, VCAM-1) and further reduces the inflammatory response. NF-κB downregulates TGF-β expression as well as anthocyanin treatment, and causes reduced ECM accumulation and limits fibrosis. Anthocyanin also reduces caspase-3 and caspase-9 levels, which further attenuates apoptosis. Abbreviations: ROS, reactive oxygen species; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; IL, interleukin; ICAM, intercellular adhesion molecule 1; VCAM, vascular cell adhesion protein 1; ECM, extracellular matrix. (-) sign indicates the inhibition/downregulation of related gene/protein. Black arrow indicates the activity of anthocyanin while red arrow indicates the subsequent event/product in the pathway.

Figure 4

Advantage of anthocyanin in nutraceutical forms.