CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity

Abstract

Aim: To investigate whether CPU86017, a berberine derivative, attenuates heart failure by blocking calcium influx and exerting its antioxidant activity. Methods: Myocardial infarction was induced in male Sprague-Dawley rats for 17 d followed by isoproterenol (ISO) (5 mg/kg, sc) treatment for 5 d to reduce cardiac function. The rats were divided into 5 groups: sham operation, myocardial infarction (MI), MI plus ISO, and co-treated (in mg/kg, po) with either propranolol (PRO, 10) or CPU86017 (80). Hemodynamic measurements were conducted, and measurements of the redox system, calcium handling proteins and endothelin (ET) system in vivo were done. Furthermore, calcium flux studies and PLB immunocytochemistry were conducted in vitro. Results: Compared to sham operation, HF was evident following MI and further worsened by ISO treatment. This occurred in parallel with downregulated mRNA and protein production of SERCA2a, PLB, and FKBP12.6, and was associated with upregulation of preproET-1, endothelin converting enzyme, and PKA mRNA production in the myocardium in vivo. Calcium leakage was induced by ISO treatment of isolated beating myocytes in vitro. These changes were attenuated by treatment with either PRO or CPU86017. PLB fluorescence in myocytes was downregulated by ISO treatment, and was relieved significantly by treatment with antioxidant aminoguanidine, ascorbic acid or CPU86017 in vitro. Conclusion: HF, calcium leakage, downregulated PLB, FKBP12.6, SERCA2a production, and upregulated PKA were caused by ISO treatment, and were abolished by CPU86017 treatment. The beneficial effects of CPU86017 are attributable to its antioxidant and calcium influx blocking effects.

Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: Role of autophagy

“…Berberine, isolated from a variety of medicinal plants, has been reported to have multiple cardioprotective effects . This traditional Chinese medicine activates autophagic proteins by inhibiting the mammalian target of rapamycin (mTOR)‐signalling pathway in HepG2 and MHCC97‐L cells .…”

Homology modeling and docking studies of <i>Plasmodium falciparum</i> telomerase reverse transcriptase with berberine and some of its derivatives

“…Berberine has treated wide range of pharmacological activities including; antihypertensive, anti-inflammatory, anti-oxidant, anti -depressant, anti-cancer, anti-diarrheal, cholagouge, hepatoprotective, antimicrobial and antimalarial (Singh et al, 2010). Berberine and its analogues have been studied extensively for their different anti-infective and pharmacological effects (Sinha and Kumar, 2009;Wang et al, 2009;Zhang et al, 2010;Qi et al, 2010, Iwazaki et al, 2010. Recent studies, have thrown light on anti-diabetic and hypolipidemic activities of the alkaloid.…”

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

“…A significant reversal of the deterioration of cardiac function and arrhythmogenic trends of affected hearts can be achieved through rescuing the depressed the FKBP12.6/12 level by blocking the activity of the ET receptors using CPU0213, a dual endothelin receptor antagonist [12,19,22] . In addition to ET antagonists, there are some compounds that specifically normalize abnormal RyR2 (and FKBP12.6/12) resulting from calcium and potassium channel blocking agents such as JTV519 [23] and CPU86017, which was developed at our laboratory [24,25] . The downregulation of FKBP12.6/12 induced by ISO is not a single event and is associated with an increase in other inflammatory factors, including ET, ROS, leptin, and an activated NADPH oxidase, in mediating the adverse effects of strong β-adrenoceptor stimulation in the heart [18,19,25] .…”