Molecular Regulation of α3β4 Nicotinic Acetylcholine Receptors by Lupeol in Cardiovascular System

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.

Phytochemical Analysis, In Vitro Free Radical Scavenging, and LDL Protective Effects of Different Solvent Fractions of Calotropis procera (R.) Br. Root Bark Extract

“…Major phytosterols identifed are lup-20(29)-en-3-ol acetate (43.71), cyclolanost-24-en-3-ol acetate (19.98), β-amyrin (14.21), α-amyrin (7.30), betulin (3.52), and urs-12-en-28oic acid (2.43). Lupeol and its esters exhibited antioxidant [95,96], hypotensive [97,98], antihyperglycemic [99,100], antidyslipidemic [100], potent anti-infammatory activity [101,102], antiangiogenic [103], anticancer [104], and nephroprotective [105] activities. Lupeol and lupeol linoleate are also demostrated protective role against hepatic lipemicoxidative injury and lipoprotein peroxidation in experimental hypercholesterolemia [106].…”

Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease

“…Data have associated nicotine exposure and AH incidence and pointed out different and interconnected mechanisms due to the high distribution and diversity of nAchR on cells involved in the complex genesis of AH, such as: Different mechanisms of action of nicotine on the vascular and cardiac autonomic nervous system have been broadly shown. For instance, nicotine directly affects the cardiac autonomic nervous system and mediates cardiac autonomic ganglion transmission [ 68 , 69 ]. Notably, nicotine during pregnancy results in autonomic dysfunction and increased blood pressure in the offspring, leading to structural–functional modifications in the arterial wall and heart [ 70 ].…”

Rare Missense Variants of the Human β4 Subunit Alter Nicotinic α3β4 Receptor Plasma Membrane Localisation

“…Because of their roles both in the periphery and in the central nervous system, α3β4 nAChRs have attracted increasing interest as potential drug targets in therapeutic applications for nicotine addiction [ 8 , 9 , 10 ], respiratory diseases [ 16 ], diabetes [ 17 ] and cardiac hypertension [ 18 ]. Hence, in recent years, a number of groups, including ours, have addressed the pharmacology, as well as the cell biology, of these receptors.…”