Stachytine Hydrochloride Improves Cardiac Function in Mice with ISO-Induced Heart Failure by Inhibiting the α-1,6-Fucosylation on N-Glycosylation of β1AR

Abstract

Background: Cardiovascular diseases have become a major public health problem that seriously threatens human health. The cumulative effects of various cardiovascular events will eventually develop into chronic heart insufficiency and even heart failure, and the β1 adrenergic receptor signal pathway plays an important role in this process. Stachytine hydrochloride is the main active ingredient of Yimucao, which is a traditional Chinese medicine used to treat gynecological diseases. Modern studies have found that stachytine hydrochloride has a good cardioprotective effect, but it is still unclear whether stachytine hydrochloride has an effect on the β1 adrenergic receptor signal pathway. The purpose of this study is to explore the effect of stachytine hydrochloride on the β1 adrenergic receptor signal pathway.Method: In this study, a continuous infusion of isoproterenol (40 mg/kg/day) was administered to mice and ventricular myocytes explored the potential mechanism of stachytine hydrochloride (12 mg/kg/day) on the β1 adrenergic receptor signal pathway in the heart. Evaluate changes in cardiac morphology and function by echocardiography, cardiac hemodynamics, and histological methods, and detect molecular changes by Western blot and immunofluorescence. Treat primary cultured adult mouse or neonatal rat ventricular myocytes with or without isoproterenol (0.1 μMol), PNGase F (10–2 units/ml), and stachytine hydrochloride (10 μMol) at different time points. Detect α-1,6-fucosylation on N-glycosylation, calcium transient, contraction, and relaxation function and related signals.Results: Stachytine hydrochloride reduces cardiac remodeling and modulates hemodynamic parameters during chronic β1 adrenergic receptor activation in vivo. The N-glycosylation of β1 adrenergic receptors decreased after continuous isoproterenol stimulation, while stachytine hydrochloride can increase the N-glycosylation of β1AR in the heart of mice with isoproterenol-induced heart failure. Decreased N-glycosylation of β1 adrenergic receptors will downregulate the cAMP/PKA signal pathway and inhibit myocardial excitation and contraction coupling. Stachytine hydrochloride significantly reduced isoproterenol-induced cardiac N-linked glycoproteins with α-1,6-fucosylation.Conclusion: Our results show that stachytine hydrochloride inhibits the synthesis of α-1,6-fucosylation on the N-terminal sugar chain by reducing α-1,6-fucosyltransferase (FUT8) and α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase A (MGAT4a), upregulating the N-glycosylation level on β1 adrenergic receptors, and maintaining cAMP/PKA signal pathway activation.

Stachydrine Hydrochloride Regulates the NOX2-ROS-Signaling Axis in Pressure-Overload-Induced Heart Failure

“…Previous studies showed that STA can improve HF in mice subjected to TAC or isoproterenol [ 5 , 6 , 19 ]. Herein, we recapitulated the cardio-protective effects of STA in TAC mice.…”

“…A component of Yimucao (Leonurus japonicas Houtt) is stachydrine hydrochloride (STA), an active alkaloid [4]. STA can attenuate HF induced through pressure overload or isoproterenol in mice [4][5][6]. Currently, the inhibition of hyperphosphorylation of calcium/calmodulindependent protein kinase II (CaMKII) is one of the anti-HF mechanisms of STA [4].…”

FUT8-Mediated Core Fucosylation Promotes the Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

“…The enzyme α-mannitosidase can affect N-glycan modification on the surface of vascular endothelial cells and thus affect the recruitment and adhesion of inflammatory cells [ 51 ]. Moreover, stachytine hydrochloride (an active ingredient in motherwort granules) can increase the number and N-glycosylation level of β1 adrenergic receptors to activate the cAMP/PKA signaling pathway and improve myocardial function [ 52 ].…”

Proteomics Revealed That Mitochondrial Function Contributed to the Protective Effect of Herba Siegesbeckiae Against Cardiac Ischemia/Reperfusion Injury

“…Furthermore, flavonoids isolated from HS aqueous extracts in the present study, such as orientin ( 30 ), vitexin ( 31 ), hyperoside ( 32 ), quercetin ( 33 ), cynaroside ( 34 ), and genistin ( 35 ), have been demonstrated to be cardioprotective during I/R, possibly through a mechanism of regulating mitochondrial function. In addition to flavonoids, other components of HS aqueous extracts, like stachydrine and 3,4-dihydroxyphenylethanol, have also been reported to protect the heart in the models of pressure overload-induced cardiac hypertrophy ( 36 ), ISO-evoked heart failure ( 37 ), and doxorubicin-induced cardiotoxicity ( 38 ). Impressively, the sulfonated diterpenoid derivatives of compounds 23–30 were first reported, and their pharmacological activities and exact chemical structures need to be further elucidated.…”