Promising Antioxidative Effect of Berberine in Cardiovascular Diseases

Abstract

Berberine (BBR), an important quaternary benzylisoquinoline alkaloid, has been used in Chinese traditional medicine for over 3,000 years. BBR has been shown in both traditional and modern medicine to have a wide range of pharmacological actions, including hypoglycemic, hypolipidemic, anti-obesity, hepatoprotective, anti-inflammatory, and antioxidant activities. The unregulated reaction chain induced by oxidative stress as a crucial mechanism result in myocardial damage, which is involved in the pathogenesis and progression of many cardiovascular diseases (CVDs). Numerous researches have established that BBR protects myocardium and may be beneficial in the treatment of CVDs. Given that the pivotal role of oxidative stress in CVDs, the pharmacological effects of BBR in the treatment and/or management of CVDs have strongly attracted the attention of scholars. Therefore, this review sums up the prevention and treatment mechanisms of BBR in CVDs from in vitro, in vivo, and finally to the clinical field trials timely. We summarized the antioxidant stress of BBR in the management of coronary atherosclerosis and myocardial ischemia/reperfusion; it also analyzes the pathogenesis of oxidative stress in arrhythmia and heart failure and the therapeutic effects of BBR. In short, BBR is a hopeful drug candidate for the treatment of CVDs, which can intervene in the process of CVDs from multiple angles and different aspects. Therefore, if we want to apply it to the clinic on a large scale, more comprehensive, intensive, and detailed researches are needed to be carried out to clarify the molecular mechanism and targets of BBR.

Keywords: Berberine; cardiovascular disease; coronary atherosclerosis; myocardial infarction/reperfusion; reactive oxygen species.

FIGURE 1

Source and functions and of berberine extract. (A) “Shennong’s Classic of Material Medical.” (B) Complete morphology of Chinese herb Huanglian. (C) Prepared officinal part of Chinese herb Huanglian. (D) Chemical structures of berberine compounds. (E) Pharmacological effects of berberine. Berberine was first documented in “Shennong’s Classic of Material Medical” in China. Berberine is isolated from Hydrastis canadensis, the Chinese herb Huanglian, and many other plants, such as the Berberidaceae and Ranunculaceae families. Berberine has many other potential pharmacological effects on various diseases, Furthermore, they have been known to have antiatherosclerosis, antimyocardial ischemia/reperfusion, and several other effects.

FIGURE 2

Chemical structure of active components of berberine. BBR is metabolized in the body by metabolic pathways (such as demethylation, glucuronidation etc) to thalifendin, berberrubine, jatrorrhizin, demethyleneberberin.

FIGURE 3

Reactive oxygen species-producing systems in cardiovascular diseases. O₂ ^●− can be generated in extracellular myocardium by NAD(P)H, uncoupled eNOS, xanthine oxidase, and mitochondrial respiration chains. H₂O₂ can be spontaneously converted into OH^●− by Fe reaction and SOD. H₂O₂ can be detoxified by GSH peroxidase, Trx peroxidase, and catalase to H₂O and O₂. The myeloperoxidase enzyme can employ H₂O₂ to oxygenize chloride to the strong oxidizer HOCl. In addition, the decoupling of eNOS reduces the production of NO^● in endothelial cells, and the decrease in the expression and activity of eNOS further aggravates the production of NO^●. NAD(P)H, nicotinamide adenine dinucleotide (phosphate); eNOS, endothelial nitric oxide synthase; NO^●, nitric oxide; O₂ ^●−, superoxide; HOCl, hypochlorite; SOD, superoxide dismutase activity; H₂O₂, hydrogen peroxide; ONOO⁻, peroxynitrite; OH^●, hydroxyl radicals; GSH, glutathione; GSSG, oxidized glutathione; GPx, glutathione peroxidase; Trx, thioredoxin.

FIGURE 4

Reactive oxygen species in the evolution of cardiovascular diseases (CVDs) and pharmacological mechanism of berberine (BBR). During the evolution of atherosclerotic plaques, the main role of berberine is to inhibit the oxidation of LDL, Ang II and inflammation, or activate AMPK and PPARγ, and further inhibiting the oxidative stress response; BBR in MI/R regulates superoxide reaction by MDA, thereby preventing excessive myocardial injury. BBR may regulate oxidative stress through the NF-κB signaling, PI3K/AKT signaling, JAK2/STAT3 signaling and so on. Oxidative stress mainly affects SR and RyR2 through ox-CaMKII and causes calcium overload, which eventually leads to AF. In terms of treatment, BBR mainly reduces the occurrence of AF by inhibiting ion channels. ROS-induced HF is mainly due to NADH/NADPH, mitochondrial disorders, XO and NOS, but the improvement of berberine in HF is mostly clinical research. Therefore, it is necessary to further study the mechanisms of BBR to treat HF through ROS and find for clinical treatment new targets.