TABLE 1.

Summary of the mechanisms of action of berberine in the treatment of CVD.

Disease	Mechanisms
Arrhythmia	Inhibits the activation of K+ current → Prolongs the effective refractory period of the atrium and the action potential duration of the atrial myocytes → Reduces the incidence of ventricular premature beats and inhibit the occurrence of VTa Hua and Wang (1994), Wang et al. (2011), Cao et al. (2012), Zhou et al. (2015). Inhibits Ca2+ current → Reduces the incidence of VT and shorten the duration of VT →Treats reperfusion arrhythmia Li et al. (1995).
Atherosclerosis	Inhibits the p38 MAPK and JNK signaling pathways → Inhibits the inflammatory response → Reduces blood lipids → Improves endothelial dysfunction → Prevents ASb Wan et al. (2018) Inhibits the ROSc production and reduces MDAd, ox-LDLe and IL-6f levels →Restores the endothelium-dependent vasodilation → Reduces the oxidative stress and inflammatory response → Improves endothelial dysfunction → Prevents AS Tan et al. (2020) . Inhibits the NF-κB and AMPK signaling pathways → Reduces macrophage activation → Inhibits foam cell formation → Reduces the levels of TCg, TGh, and LDL-Ci Huang et al. (2012), Chi et al. (2014), Pei et al. (2019), Ke et al. (2020). Inhibits the expression of gp91phox protein and enhance the activity of SODj → Reduces the superoxide levels → Inhibits oxidative stress → Prevents AS Sarna et al., (2010). Inhibits the activation of ERK1/2 and the phosphorylation of AKT → Inhibits smooth muscle cell proliferation and migration → Prevents AS and arterial restenosis Cho et al. (2005), Lee et al. (2006). Activates the PPARα-NOk signaling pathway/Inhibitis the PI3K signaling pathway/Inhibits the PDI/MAPK/ERS system → Inhibits VSMCl proliferation Ma et al. (2015), Qiu et al. (2017), Wang et al. (2020).
Hyperlipidemia	Regulates the PCSK9-LDLR pathway → Reduces the level of LDLR protein in the liver → Reduces the plasma concentrations of LDL-C, TG, and TC Xiao et al. (2012) Regulates the HNF-4α-miR122 pathway → Reduces gluconeogenesis and lipid metabolism changes in the liver Wei S et al. (2016). Regulates the AMPKα-SREBP pathway → Prevents olanzapine-induced lipid metabolism disorders Li et al. (2016).
Hypertension	Increases the expression of NO → Promotes vasodilation → Maintains arterial elasticity and improves endothelial function Zhang et al. (2018), Zhang et al. (2020). Inhibits the TRPV4 channels → Relaxes the vascular smooth muscle → Treats hypertension and vascular aging Ueda et al. (2011), Wang et al. (2015a). Inhibits the MyD88-TLR4 pathway → Inhibits endothelial apoptosis → Protects the vascular endothelium from damage Chung et al. (2004), Romero et al. (2011), Wang and Ding (2015). Inhibits the CXCR4/JAK-2 signaling pathway → Protects endothelial cells Sainz and Sata (2007), Shao et al. (2018). Activates the AMPK pathway → Inhibits endoplasmic reticulum stress in endothelial cells → Protects vascular function Schröder and Kaufman (2005) Liu et al. (2015).
Ischemic heart disease	Regulates the activity of AMPK in non-ischemic and ischemic regions of the heart → Reduces infarct areas during IRm injury → Improves cardiac function Chang et al. (2012) Increases the expression of miR-29b → Activates Akt in endothelial cells → Promotes the proliferation and migration of endothelial cells → Improves myocardial remodeling Van der Laan et al. (2009), Zhu et al. (2017) Activates the AMPK, PI3K-Akt-eNOS, Notch1/Hes1-PTEN/Akt, AK2/STAT3, and Smad7 pathways → Reduces apoptosis → Reduces MI/Rn injury Chen et al. (2014), Yu et al. (2015), Zhao et al. (2016), Yao et al. (2018) Activates the SIRT1 pathway → Reduces oxidative stress and cardiac inflammation → Reduces MI/R injury Yu et al. (2016) Regulates the HIF-1α/BNIP3 pathway → Promotes mitochondrial autophagy, promotes cardiomyocyte proliferation, and inhibits cardiomyocyte apoptosis → Reduces MI/R injury Zhu et al. (2020). Inhibits caspase-3 protein expression → Increases VEGFo, FGF2p and TSP-1q expression → Reduces myocardial infarct size Banaei et al. (2020).
Myocarditis and cardiomyopathy	Inhibits the p38 MAPK and JNK pathway → Inhibits CVB3r replication → Inhibits macrophage infiltration and pro-inflammatory factors production → Reduces cardiac injury Dai et al. (2017), Dai et al. (2020b) Inhibits the Th17/Th1 cell differentiation → Improves left ventricular function → Improves EAMs Liu et al. (2016) Increases the Sirt3 protein levels → Inhibits caspase 9 and 3-like activation → Attenuates cardiotoxicity Coelho et al. (2017) Inhibits the elevation of intracellular Ca2+ → Alleviates mitochondrial dysfunction → Decreases CKt, CK-MBu and MDA levels and increases SOD and CATv levels → Improves cardiac dysfunction Xiong et al. (2018) Upregulates of SIRT1 and downregulates the p66shc expression → Inhibits the ROS production, apoptosis and mitochondrial damage → Improves cardiac dysfunction Wu et al., (2019). Increases the cardiac AMPK and AKT activity and inhibits GSK3β activity → Inhibits cardiac fibrosis → improves cardiac function Chang et al. (2015).
Heart failure	Reduces the end-diastolic pressure of the right atrium and left ventricle, increases the left ventricular ejection fraction, and decreases the arteriovenous oxygen difference → Reduces the incidence of ventricular arrhythmias → Improves quality of life Marin-Neto et al. (1988), Zeng et al. (2003) Decreases the Ca2+ levels in myocardial cells → Decreases the left ventricular end-diastolic pressure Zhang et al. (2008) Regulates the mTOR pathway → Inhibits the phosphorylation of ERK1/2 and p38 → Enhances autophagy and inhibits endoplasmic reticulum stress → Prevents myocardial hypertrophy and apoptosis Li et al. (2014), Hashemzaei et al. (2017) Activates the Pak1 pathway → Inhibits the upregulation of Fbxo32 → Treats myocardial hypertrophy Tsui et al. (2015) Upregulates the PINK1/Parkin-mediated mitochondrial autophagy → Inhibits the cardiomyocyte apoptosis and mitochondrial damage → Improves the cardiac dysfunction and myocardial hypertrophy Abudureyimu et al. (2020).

a, ventricular tachycardia; b, Atherosclerosis; c, reactive oxygen species; d, malondialdehyde; e, oxidized low-density lipoprotein; f, interleukin-6; g, Total cholesterol; h, Triglyceride; i, LDL cholesterol; j, superoxide dismutase; k, Nitric oxide; l, vascular smooth muscle cells; m, Ischemia-reperfusion; n, myocardial ischemia/reperfusion; o, vascular endothelial cell growth factor; p, fibroblast growth factor-2; q, platelet response factor-1; r, coxsackievirus B3; s, experimental autoimmune myocarditis; t, creatine kinase; u, creatine kinase isoenzyme; v, catalase.