Stachydrine hydrochloride alleviates pressure overload-induced heart failure and calcium mishandling on mice

Chen, Huihua; Wang, Si-Ning; Cao, T.; Zheng, Jiali; Tian, Jing; Shan, Xiaoli; Zhao, Pei; Guo, Wei; Xu, Ming; Zhang, Chen; Lü, Rong

doi:10.1016/j.jep.2019.112306

Cited by 23 publications

(19 citation statements)

References 33 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Wei

Pan

et al. 2022

Front. Cardiovasc. Med.

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BackgroundMyocardial ischemia/reperfusion (I/R) injury is the main obstacle to percutaneous coronary intervention, lacking effective therapeutic measures in a clinical setting. Herba Siegesbeckiae (HS) is a traditional herb with multiple pharmacological activities and evidence of cardiovascular protection. However, few data are available regarding the role of HS in cardiac I/R. This study aimed to explore the effect and underlying mechanism of HS aqueous extract on cardiac I/R injury.Materials and MethodsHerba Siegesbeckiae aqueous extract was prepared and analyzed by UHPLC-MS/MS. After intragastric administration of HS once daily for 7 days, male Sprague-Dawley rats were subjected to 30 min occlusion of the left anterior descending coronary artery followed by 120 min reperfusion to elicit I/R. Various parameters like myocardial infarction and apoptosis, 12-lead ECG and hemodynamics, cardiac morphology and myocardial enzymes, quantitative proteomics, mitochondrial ultrastructure and electron transport chain (ETC) function, oxidative stress and antioxidation, and NLRP3 inflammasome and inflammation were evaluated.ResultsThe chemical constituents of HS aqueous extract were mainly divided into flavonoids, diterpenoids, and organic acids. In vivo, HS aqueous extract notably alleviated myocardial I/R injury, as evidenced by a reduction in infarct size, apoptotic cells, and cardiac lesion enzymes; decline of ST-segment elevation; improvement of cardiac function; and preservation of morphology. Quantitative proteomics demonstrated that HS reversed the alteration in the expression of Adgb, Cbr1, Decr1, Eif5, Uchl5, Lmo7, Bdh1, Ckmt2, COX7A, and RT1-CE1 after I/R. In addition, HS preserved myocardial ultrastructure and restored the function of mitochondrial ETC complexes following exposure to I/R; HS significantly suppressed I/R-elicited increase of ROS, RNS, MDA, and 8-OHdG, restrained the acetylation of MnSOD, and recovered the activity of MnSOD; and HS reversed I/R-induced elevation of NLRP3 inflammasome and inhibited the release of inflammatory factors and pyroptosis.ConclusionHerba Siegesbeckiae aqueous extract ameliorated cardiac I/R injury, which is associated with mitigating oxidative stress, suppressing NLRP3 inflammasome, and restoring mitochondrial function by regulating the expression of Adgb, Cbr1, Decr1, Eif5, Uchl5, Lmo7, Bdh1, Ckmt2, COX7A, and RT1-CE1.

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Section: Discussionmentioning

confidence: 99%

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

Wei

Pan

et al. 2022

Front. Cardiovasc. Med.

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“…Stachydrine hydrochloride alleviated phenylephrine-induced elevated levels of sarcomere contraction, calcium transients, and calcium sparks. Moreover, among a series of proteins in the calcium signaling cascade, the hyperphosphorylation of CaMKII, RyR2, and PLN was blocked by stachydrine hydrochloride, which facilitated the binding of FKBP12.6 to RyR2 (Chen et al, 2020). Stachydrine hydrochloride also decreased the level of SR calcium leakage into the cytoplasm, and the underlying mechanism might be related to the reduction of transverse aorta constriction (TAC)/PE-induced hyperphosphorylation of CaMKII (Chen et al, 2020).…”

Section: Heart Failurementioning

confidence: 97%

“…In a failing heart, the Ca 2+ transient amplitude of cardiomyocytes is decreased, together with enhanced SR Ca 2+ leakage and reduced SR Ca 2+ uptake (Balke and Shorofsky, 1998;Luo and Anderson, 2013). In the early stages of HF, CaMKII promotes the phosphorylation of RyR2 at serine 2814/2815, leading to abnormal Ca 2+ signals, such as a high level of calcium sparks (Chen et al, 2020). Many active ingredients of TCM have played an important role in anti-heart failure by inhibiting calcium signal disorder and reducing Ca 2+ overload (Li et al, 2018a;Cheng et al, 2018;) (Table 4).…”

Section: Heart Failurementioning

confidence: 99%

“…Moreover, among a series of proteins in the calcium signaling cascade, the hyperphosphorylation of CaMKII, RyR2, and PLN was blocked by stachydrine hydrochloride, which facilitated the binding of FKBP12.6 to RyR2 (Chen et al, 2020). Stachydrine hydrochloride also decreased the level of SR calcium leakage into the cytoplasm, and the underlying mechanism might be related to the reduction of transverse aorta constriction (TAC)/PE-induced hyperphosphorylation of CaMKII (Chen et al, 2020). An in vivo model of abdominal aortic constriction in rats and an in vitro model of ISO-treated H9C2 cells have been used to study the beneficial effect of baicalein in Scutellaria baicalensis on myocardial function (Zhao et al, 2016), and the results indicated that baicalein regulated the expression and activity of SERCA and RyR2 to maintain calcium balance in the heart.…”

Section: Heart Failurementioning

confidence: 99%

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Therapeutic Effects of Traditional Chinese Medicine on Cardiovascular Diseases: the Central Role of Calcium Signaling

Zhang

et al. 2021

Front. Pharmacol.

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Calcium, as a second messenger, plays an important role in the pathogenesis of cardiovascular diseases (CVDs). The malfunction of calcium signaling in endothelial cells and vascular smooth muscle cells promotes hypertension. In cardiomyocytes, calcium overload induces apoptosis, leading to myocardial infarction and arrhythmias. Moreover, the calcium–calcineurin–nuclear factor of activated T cells (NFAT) pathway is essential for expressing the cardiac pro-hypertrophic gene. Heart failure is also characterized by reduced calcium transient amplitude and enhanced sarcoplasmic reticulum (SR) calcium leakage. Traditional Chinese medicine (TCM) has been used to treat CVDs for thousands of years in China. Because of its multicomponent and multitarget characteristics, TCM's unique advantages in CVD treatment are closely related to the modulation of multiple calcium handling proteins and calcium signaling pathways in different types of cells involved in distinct CVDs. Thus, we systematically review the diverse mechanisms of TCM in regulating calcium pathways to treat various types of CVDs, ranging from hypertrophic cardiomyopathy to diabetic heart disease.

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“…Because it can improve hemodynamics and hemorheology, it has a protective effect on protecting the cardiovascular system ( Liu et al, 2012 ). Our research group conducted a series of studies on the effect of stachytine hydrochloride (Sta), the main active component of Yimucao, and found that Sta can inhibit norepinephrine ( Zhang et al, 2014 ), phenylephrine ( Zheng et al, 2020 ), and TAC-induced myocardial hypertrophy; reduce calcium leakage; maintain calcium homeostasis; inhibit myocardial fibrosis ( Liu et al, 2019 ); and improve cardiac function ( Chen et al, 2020 ). However, the molecular target of Sta is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Guo

Yang

et al. 2022

Front. Pharmacol.

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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.

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Stachydrine hydrochloride alleviates pressure overload-induced heart failure and calcium mishandling on mice

Cited by 23 publications

References 33 publications

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

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

Therapeutic Effects of Traditional Chinese Medicine on Cardiovascular Diseases: the Central Role of Calcium Signaling

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

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