Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics

Abstract

Cardiovascular and metabolic diseases (CVMD) are the leading causes of death worldwide, underscoring the urgent necessity to develop new pharmacotherapies. Berberine (BBR) is an eminent component of traditional Chinese and Ayurvedic medicine for more than 2000 years. Recently, BBR has attracted much interest for its pharmacological actions in treating and/or managing CVMD. Recent discoveries of basic, translational and clinical studies have identified many novel molecular targets of BBR (such as AMPK, SIRT1, LDLR, PCSK9, and PTP1B) and provided novel evidences supporting the promising therapeutic potential of BBR to combat CVMD. Thus, this review provides a timely overview of the pharmacological properties and therapeutic application of BBR in CVMD, and underlines recent pharmacological advances which validate BBR as a promising lead drug against CVMD.

Keywords: berberine; cardiovascular diseases; metabolic diseases; targets; therapeutics.

Figure 1

Therapeutic potential of BBR in cardiometabolic diseases. Current researches support that BBR may play a therapeutic role in the treatment of cardiovascular disease (including atherosclerosis, heart failure, myocardial infarction, arrhythmia, abdominal aortic aneurysm, stroke) and metabolic diseases (including nonalcoholic fatty liver, obesity, diabetes and its cardiovascular complications).

Figure 2

Selected metabolites of BBR in human. BBR is metabolized in the body by metabolic pathways (such as demethylation, glucuronidation etc) to thalifendin, berberrubine, jatrorrhizin, demethyleneberberin.

Figure 3

Anti-atherosclerotic effects of BBR. The role of BBR in inhibiting atherosclerosis includes improving endothelial dysfunction; inhibiting smooth muscle cell proliferation and migration; reducing monocyte adhesion, macrophage inflammation and cholesterol aggregation, foam cell formation, and platelet aggregation. Abbreviations: low density lipoprotein (LDL); oxidized LDL (oxLDL).

Figure 4

Effects of BBR on heart failure, arrhythmia, myocardial ischemia and abdominal aortic aneurysm. Specifically, BBR prevents ischemia/reperfusion injury via its positive inotropic activity, increased phosphorylation of Bad, decreased production of pro-inflammatory mediators (IL-6, IL-1β, and TNFα), reducing oxidative stress, blood-pressure lowering, anti-apoptotic effects and protective effects against endoplasmic reticulum stress. BBR prevents heart failure by increasing cardiac output, and decreasing LVEDP and DBP. BBR prevents arrhythmia by reducing ventricular premature beats and tachycardia. BBR prevents abdominal aortic aneurysm by reducing vascular remodeling and pressure, reducing aortic stiffness, modulating lipid level, and increase aortic pulse wave velocity. ↑indicates increase or activation, and ↓indicates decrease or suppression. Abbreviations: Bad, Bcl-2-associated death promoter; diastolic blood pressure (DBP), interleukin-1β (IL-1β), interleukin-6 (IL-6), left ventricular end-diastolic pressure (LVEDP) , peak rate of rise of left ventricular pressure (+dp/dt), tumor necrosis factor α (TNFα).

Figure 5

Pharmacological effects of berberine in treating diabetes (A) and its cardiovascular complications (B). BBR exerts protective effects in diabetes by ameliorating insulin resistance, modulating lipid metabolism and gut microbiota, inhibiting α-amylase and α-glucosidase activity. BBR also prevents cardiovascular complications associated with diabetes, such as diabetic cardiomyopathy, cardiac fibrosis, endothelial injury, endothelial progenitor cell dysfunction, and vasoconstriction. ↑indicates increase or activation, and ↓indicates decrease or suppression. Abbreviations: AMP protein kinase (AMPK), α-smooth muscle actin (α-SMA), cholesterol (TC), collagen (Col), connective tissue growth factor (CTGF), dinucleotide phosphate-oxidase (NOX), endothelial nitric oxide synthase (eNOS), endothelial progenitor cells (EPCs), fasting blood glucose (FBG), fasting serum insulin (FSI), glycogen synthase kinase 3β (GSK3β), heme oxygenase-1 (HO-1), insulin-like growth factor-1 receptor (IGF-1R), matrix metalloproteinase (MMP), non-alcoholic fatty liver disease (NAFLD), nitric oxide (NO), nuclear factor erythroid 2-related factor 2 (Nrf2), phosphatidylcholine (PC), phosphatidylethanolamine (PE), protein kinase B (Akt), sphingolipid (SM), triglyceride (TG), transforming growth factor β1 (TGFβ1).

Figure 6

Molecular targets of BBR. BBR exerts its pharmacological effects by regulating the expression of genes/proteins responsible for transcription factors, enzymes, growth factors, cell survival/proliferative proteins, metastatic/invasion molecules, platelet activation, inflammatory cytokines, protein kinases, apoptotic proteins, receptors, and the others. By targeting these molecules, BBR prevents the development of multiple cardiovascular and metabolic diseases. ↑indicates increase or activation, and ↓indicates decrease or suppression. Abbreviations: arachidonic acid (AA), ATP-binding membrane cassette transport protein A1 (ABCA1), angiotensin-converting enzyme (ACE), adenosine diphosphate (ADP), adipocyte enhancer-binding protein 1 (AEBP1), apoptotic protease-activating factor 1 (Apaf-1), adipose triglyceride lipase (ATGL), aldose reductase (AR), calmodulin-dependent kinase II (CaMKK II), C‑C motif ligand 19 (CCL19), the cluster of differentiation 18 (CD18), the cluster of differentiation 36 (CD36), carbohydrate responsive element binding protein (ChREBP), MB isoenzyme of creatine kinase (CK-MB), type 1 collagen (Col1), C-reactive protein (CPR), connective tissue growth factor (CTGF), 1,2-diacyl-sn-glycerol (DAG), endoplasmic reticulum (ER), extracellular MMP inducer (EMMPRIN), endothelin 1 receptor(ET-1R), fatty acid synthase (FAS), fibroblast growth factor 21 (FGF21), fasting-induced adipose factor (FIAF), farnesoid X receptor (FXR), glucose-6-phosphatase (G6Pase), glucagon-like peptide 1 receptor (GLP-1R), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), hepatocyte nuclear factor-4α (HNF-4α), intercellular adhesion molecule-1 (ICAM-1), IκB kinase β (IKKβ), interleukin-1β (IL-1β), interleukin-6 (IL-6), insulin receptor (InsR), insulin receptor substrate 2 (IRS-2), N-terminal kinase (JNK), lactate dehydrogenase (LDH), LDL receptor (LDLR), lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), monocyte chemotactic protein-1 (MCP-1), migration inhibitory factor (MIF), matrix metalloproteinases (MMPs), mitochondrial pyruvate carrier (MPC), microsomal triglyceride transfer protein (MTTP), nuclear factor-kappaB (NF-κB), Nod-like receptor family pyrin domain containing3 (NLRP3), nitric oxide (NO), nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), nuclear factor erythroid-2-related factor-2 (Nrf2), protein S6 kinase (p70S6K), proprotein convertase subtilisin/kexin type 9 (PCSK9), ribosomal proliferating cell nuclear antigen (PCNA), P-glycoprotein (P-gp), phosphoenol pyruvate carboxykinase (PEPCK), phosphatidylinositol 3 kinase (PI3K), peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), protein tyrosine phosphatase1B (PTP1B), activate silent information regulator 1 (SIRT1), super oxide dismutase (SOD), scavenger receptor class B type I (SR-BI), sterol regulatory element binding protein (SREBP), 1,2,3-triacyl-sn-glycerol (TAG), tissue growth factor-β1(TGFβ1), Toll-like receptor 4 (TLR4), tumor necrosis factor α (TNFα), TNF receptor-associated factor 2 (TRAF2), transient receptor potential vanilloid 4 (TRPV4), uncoupling protein 2 (UCP2), urokinase-type plasminogen activator (u-PA), vascular cell adhesion molecule-1 (VCAM-1).

Figure 7

Derivatives of BBR in treating cardiovascular and metabolic diseases. Currently, there are several derivatives being developed based on BBR structural skeleton. These derivatives, such as dihydroberberine, 6-protoberberine, Raisanberine, IMB-Y53, and berberine-baicaline hybrids etc have therapeutic potential in treating cardiovascular and metabolic diseases.