Abstract
Cardiovascular disease (CVD) occurs globally and has a high mortality rate. The highest risk factor for developing CVD is high blood pressure. Currently, natural products are emerging for the treatment of hypertension to avoid the side effects of drugs. Among existing natural products, lupeol is known to be effective against hypertension in animal experiments. However, there exists no study regarding the molecular physiological evidence against the effects of lupeol. Consequently, we investigated the interaction of lupeol with α3β4 nicotinic acetylcholine receptors (nAChRs). In this study, we performed a two-electrode voltage-clamp technique to investigate the effect of lupeol on the α3β4 nicotine acetylcholine receptor using the oocytes of Xenopus laevis. Coapplication of acetylcholine and lupeol inhibited the activity of α3β4 nAChRs in a concentration-dependent, voltage-independent, and reversible manner. We also conducted a mutational experiment to investigate the influence of residues of the α3 and β4 subunits on lupeol binding with nAChRs. Double mutants of α3β4 (I37A/N132A), nAChRs significantly attenuated the inhibitory effects of lupeol compared to wild-type α3β4 nAChRs. A characteristic of α3β4 nAChRs is their effect on transmission in the cardiac sympathetic ganglion. Overall, it is hypothesized that lupeol lowers hypertension by mediating its effects on α3β4 nAChRs. The interaction between lupeol and α3β4 nAChRs provides evidence against its effect on hypertension at the molecular-cell level. In conclusion, the inhibitory effect of lupeol is proposed as a novel therapeutic approach involving the antihypertensive targeting of α3β4 nAChRs. Furthermore, it is proposed that the molecular basis of the interaction between lupeol and α3β4 nAChRs would be helpful in cardiac-pharmacology research and therapeutics.
Highlights
Cardiovascular disease (CVD) is a major global cause of mortality and of global interest due to the increasing trend of cardiovascular risk factors
In the two-electrode voltage-clamp experiments, when 100 μM of acetylcholine was employed instead of the ND96 buffer, an inward current was generated in the oocytes injected with α3β4 Nicotinic acetylcholine receptors (nAChRs) RNA
Treatments with lupeol and mecamylamine (MEC) alone showed no change in current, but cotreatment of lupeol (30 μM) with acetylcholine (ACh) of 100 μM significantly inhibited IACh compared with the treatment of aannddrreegguulalatotorryyeeffffeecctstsoof flulpuepoelool nonthtehαe3αβ34βn4icnoitcionticinaicceatycelcthyloclhinoelirneecerpectoeprst.o(rAs.) (ACh) (100 μM) alone, like official antagonist MEC (Figure 1; n = 4–5 from three different frogs)
Summary
Cardiovascular disease (CVD) is a major global cause of mortality and of global interest due to the increasing trend of cardiovascular risk factors. Nicotinic acetylcholine receptors (nAChRs) mediate cardiac ganglion transmission in the autonomic nervous system concerning CVD [4,5]. These nAChRs are composed of five protein subunits [6] that form a functional homogeneous receptor, such as α7, α9, and α10. Lupeol exerts enormous pharmacological effects on the treatment of chronic vascular diseases such as hyperlipidemia, high blood pressure, cancer, and antiviral and anti-inflammatory conditions [13,14,15]. Lupeol is effective against hypertension and obesity, which are the highest risk factors for CVD [16]. It was observed that lupeol inhibited the activity of α3β4 nAChRs in a concentration-dependent, voltage-independent, noncompetitive, and reversible manner
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