Exposure to the natural alkaloid Berberine affects cardiovascular system morphogenesis and functionality during zebrafish development

Abstract

The plant-derived natural alkaloid berberine displays therapeutic potential to treat several pathological conditions, including dyslipidemias, diabetes and cardiovascular disorders. However, data on berberine effects during embryonic development are scarce and in part controversial. In this study, using zebrafish embryos as vertebrate experimental model, we address the effects of berberine treatment on cardiovascular system development and functionality. Starting from the observation that berberine induces developmental toxicity and pericardial edema in a time- and concentration-dependent manner, we found that treated embryos display cardiac looping defects and, at later stages, present an abnormal heart characterized by a stretched morphology and atrial endocardial/myocardial detachment. Furthermore, berberine affected cardiac functionality of the embryos, promoting bradycardia and reducing the cardiac output, the atrial shortening fraction percentage and the atrial stroke volume. We also found that, during development, berberine interferes with the angiogenic process, without altering vascular permeability. These alterations are associated with increased levels of vascular endothelial growth factor aa (vegfaa) mRNA, suggesting an important role for Vegfaa as mediator of berberine-induced cardiovascular defects. Altogether, these data indicate that berberine treatment during vertebrate development leads to an impairment of cardiovascular system morphogenesis and functionality, suggesting a note of caution in its use during pregnancy and lactation.

Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases

“…Berberine is a multifunctional, natural product with therapeutic potential in vascular diseases, including cardiovascular disease, atherosclerosis, hypertension, cerebrovascular disease, diabetes and associated complications, intestinal vascular disease and cancer ( Zhu et al, 2018 ; Martini et al, 2020 ; Yin et al, 2021 ). The present review has shown the excellent protective effect of berberine in diverse vascular diseases by preserving vascular endothelial cells, improving vascular remodeling and vasoconstriction, and suppressing inflammation, oxidative stress, autophagy, and apoptosis, based on recent in vitro and in vivo experimental reports ( Figure 2 ).…”

“…Berberine is a multifunctional, natural product with therapeutic potential in vascular diseases, including cardiovascular disease, atherosclerosis, hypertension, cerebrovascular disease, diabetes and associated complications, intestinal vascular disease and cancer (Zhu et al, 2018;Martini et al, 2020;Yin et al, 2021).…”

“…Treatment with berberine in mice with MI injury was shown to lead to elevated miR-29b can activate the protein kinase B (Akt) signaling pathway, thus promoting angiogenesis and cell proliferation and migration to improve heart function ( Zhu et al, 2017 ). A study in zebrafish embryos revealed that the level of VEGF-aa mRNA was up-regulated by berberine, which interfered with the angiogenic process, promoting bradycardia and reducing the cardiac output, atrial shortening fraction percentage, and atrial stroke volume ( Martini et al, 2020 ). A complex hemodynamic pathological phenomenon exists in ischemia and reperfusion injury that can engage the metabolic and inflammatory machinery in the development of various disorders, including heart failure ( Raza et al, 2020 ).…”

“…A study in zebrafish embryos revealed that the level of VEGF-aa mRNA was up-regulated by berberine, which interfered with the angiogenic process, promoting bradycardia and reducing FIGURE 2 | Biological activities and potential pathways of berberine on vascular diseases. Abbreviations: Akt, protein kinase B; AMPK, AMP-activated protein kinase; AP-1, activator protein 1; Bax, Bcl-2 associated X protein; Bcl-2, B-cell lymphoma 2; BMPR-2, bone morphogenetic protein type 2; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; HIF-1α, hypoxia-inducible factor 1α; JAK-2, janus kinase 2; MAPK, mitogen-activated protein kinase; MMP-2, matrix metalloprotease 2; NF-κB, nuclear factor κB; PI3K, phosphoinositide 3-kinase; SIRT-1, silent information regulator 1; signal the cardiac output, atrial shortening fraction percentage, and atrial stroke volume (Martini et al, 2020). A complex hemodynamic pathological phenomenon exists in ischemia and reperfusion injury that can engage the metabolic and inflammatory machinery in the development of various disorders, including heart failure (Raza et al, 2020).…”

Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer

“…Previous studies have revealed that BBR is cardiotoxic, leading to total amplitude and beating rate inhibition at 10 μM in cardiomyocytes ( Zhang et al, 2018 ). Animal experiments have suggested that BBR exerts toxic and teratogenic effects in developing zebrafish embryos at 400 mg/L for a-48 h administration, as evidenced by pericardial edema, damaged heart morphogenesis, vascular defects, and death ( Martini et al, 2020 ). BBR treatment during vertebrate development leads to the impairment of cardiovascular system morphogenesis and functionality, suggesting it should be used with caution during pregnancy and lactation.…”