Abstract
Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms of β-CTX as a β-blocker and its association with the β-adrenergic pathway. The effects of β-CTX on isolated cardiac myocyte functions, calcium homeostasis, the phosphorylation level of targeted proteins, and the myofibrillar ATPase activity were studied. Healthy Sprague Dawley rats were used for cardiomyocytes isolation. Like propranolol, β-CTX attenuated the cardiomyocyte inotropy and calcium transient alterations as induced by isoproterenol stimulation. In contrast, these effects were not observed in forskolin-treated cells. Interestingly, cardiomyocytes treated with β-CTX showed no changes in phosphorylation level at any PKA-targeted sites in the myofilaments as demonstrated in Western blot analysis. The skinned fibers study revealed no change in myofilament kinetics by β-CTX. However, this protein exhibited the direct inhibition of myofibrillar ATPase activity with calcium de-sensitization of the enzyme. In summary, the negative inotropic mechanism of β-CTX was discovered. β-CTX exhibits an atypical β-blocker mechanism. These properties of β-CTX may benefit in developing a novel agent aid to treat hypertrophic cardiomyopathy.
Highlights
Beta-cardiotoxin (β-CTX), is a non-enzymatic protein containing in the venom of the king cobra (Ophiophagus hannah)[1]
Reduced the p-Ser[16] and Thr[17] indicates the blockade of the β2 adrenergic receptors (β-ARs) (p < 0.05). These results demonstrated that β-CTX was not associated with the phosphorylation of proteins targeted in β-AR stimulation
There are only three publications regarding the β-CTX in the PubMed database. β-CTX was shown to bind to both β1- and β2-adrenergic receptors in vitro with the negative inotropic effect in vivo[19]
Summary
Beta-cardiotoxin (β-CTX), is a non-enzymatic protein containing in the venom of the king cobra (Ophiophagus hannah)[1]. Our recent study demonstrated the calcium-independent negative inotropic effects of β-CTX in the isolated cardiomyocyte[3] (i.e., β-CTX reduced myocyte contractility without alteration in calcium transient at the basal state), indicating the possibility of involvement of a non-classical-β-adrenergic pathway by β-CTX. The objectives of the study were (i) to determine the effects of β-CTX on isolated cardiomyocyte functions with the presence of isoproterenol (ISO), the standard β-agonist, and forskolin (FSK), the adenylyl cyclase activator, (ii) to evaluate the alteration of phosphorylated proteins responsive in the β-adrenergic pathway and (iii) to study the direct effects of the compound on myofilament Ca2+-sensitivity and enzyme activity
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