scholarly journals Shenxian-Shengmai Oral Liquid Improves Sinoatrial Node Dysfunction through the PKC/NOX-2 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Heng Zhang ◽  
Miao Hao ◽  
Lingkang Li ◽  
Keyan Chen ◽  
Jing Qi ◽  
...  
Keyword(s):  
Heart Rate ◽  
Signaling Pathway ◽  
Sinoatrial Node ◽  
Cardiac Conduction ◽  
Potential Mechanism ◽  
Cardiac Syncope ◽  
Common Causes ◽  
Oral Liquid ◽  
Masson Staining

Sick sinus syndrome (SSS) is one of the common causes of cardiac syncope and sudden death; the occurrence of SSS is associated with the accumulation of ROS in the sinoatrial node (SAN). Shenxian-shengmai (SXSM) is a traditional Chinese medicine available as oral liquid that causes a significant increase in heart rate. The objective of this study is to observe the improvement of SXSM on SAN function in SSS mice and explore its potential mechanism. In the current study, SSS was simulated in mice by inducing SAN dysfunction using a micro-osmotic pump to inject angiotensin II (Ang II). The mouse model with SSS was used to determine the effect of SXSM on SAN function and to explore its potential mechanism. Furthermore, the HL-1 cell line, derived from mouse atrial myocytes, was used to simulate SAN pacemaker cells. Our results indicated that SXSM significantly increased the heart rate of SSS mice by reducing the AngII-induced accumulation of ROS in the SAN and by inhibiting the expression of HDAC4, thereby reducing the loss of HCN4, a critical component of the cardiac conduction system. MASSON staining revealed a reduction of SAN damage in SSS mice that were treated with SXSM compared with controls. In vitro experiments showed that AngII treatment caused an upregulation of the PKC/NOX-2 signaling pathway in HL-1 cells which could be prevented by pretreatment with SXSM. The protective effect of SXSM was attenuated upon treatment with the PCK agonist PMA. In conclusion, SXSM reduced the AngII-induced accumulation of ROS in the SAN through the PKC/NOX2 signaling pathway, improving the functioning of the SAN and preventing the decrease of heart rate in SSS mice.

scholarly journals Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node

2010 ◽  
Vol 136 (3) ◽  
pp. 247-258 ◽  
Author(s):  
Zhandi Liao ◽  
Dean Lockhead ◽  
Eric D. Larson ◽  
Catherine Proenza
Keyword(s):  
Heart Rate ◽  
Protein Kinase ◽  
Cyclic Nucleotide ◽  
Sinoatrial Node ◽  
Voltage Dependence ◽  
C Terminus ◽  
Sympathetic Regulation ◽  
Direct Binding ◽  
End Effectors

The sympathetic nervous system increases heart rate by activating β adrenergic receptors and increasing cAMP levels in myocytes in the sinoatrial node. The molecular basis for this response is not well understood; however, the cardiac funny current (If) is thought to be among the end effectors for cAMP signaling in sinoatrial myocytes. If is produced by hyperpolarization-activated cyclic nucleotide–sensitive (HCN4) channels, which can be potentiated by direct binding of cAMP to a conserved cyclic nucleotide binding domain in the C terminus of the channels. β adrenergic regulation of If in the sinoatrial node is thought to occur via this direct binding mechanism, independent of phosphorylation. Here, we have investigated whether the cAMP-activated protein kinase (PKA) can also regulate sinoatrial HCN4 channels. We found that inhibition of PKA significantly reduced the ability of β adrenergic agonists to shift the voltage dependence of If in isolated sinoatrial myocytes from mice. PKA also shifted the voltage dependence of activation to more positive potentials for heterologously expressed HCN4 channels. In vitro phosphorylation assays and mass spectrometry revealed that PKA can directly phosphorylate at least 13 sites on HCN4, including at least three residues in the N terminus and at least 10 in the C terminus. Functional analysis of truncated and alanine-substituted HCN4 channels identified a PKA regulatory site in the distal C terminus of HCN4, which is required for PKA modulation of If. Collectively, these data show that native and expressed HCN4 channels can be regulated by PKA, and raise the possibility that this mechanism could contribute to sympathetic regulation of heart rate.

scholarly journals A Network Pharmacology-based Study of the Potential Mechanism of Bushenhuoxue Formula in Treating Osteoarthritis

2020 ◽  
Author(s):  
Xiong Wen ◽  
Cai Xianhua
Keyword(s):  
Signaling Pathway ◽  
Protein Interactions ◽  
Diabetic Complications ◽  
Target Genes ◽  
Endocrine Resistance ◽  
Network Pharmacology ◽  
Potential Mechanism ◽  
Apoptosis Rate

Abstract Background: To investigate the potential mechanism underlying the efficacy of BuShenHuoXue (BSHX) formula on Osteoarthritis (OA) and its molecular mechanism. Materials and Methods: Data as for bioactive chemicals of individual herb in BSHX formula and their targets were collected from Traditional Chinese Medicine Systems Pharmacology database and OA-associated targets from Gene Expression Omnibus database, compound-disease target network and protein-protein interactions network were built, picturized and analyzed by Cytoscape. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment of key targets were carried out and analyzed to probe into the core pathway and their main functions further. The chondrocytes of SD rats were cultured in vitro, and 50μg/ml IL-1βwas added to the chondrocytes to induce apoptosis. Different concentrations of quercetin were added to the experimental group and the apoptosis rate of chondrocytes, the difference of the expression of SELE, MMP2, and COL1 genes and their protein expression level were further detected. Results: A total of 104 candidate chemicals and 42 crossing targets were screened out. Leading target genes are PTGS2, NCOA2 and HSP90AA1, whereas quercetin and luteolin are principal ingredients. Potential pathways against OA are AGE-RAGE signaling pathway in diabetic complications, Relaxin signaling pathway, IL-17 signaling pathway, Tyrosine metabolism and Endocrine resistance. Our study showed that quercetin could inhibit the apoptosis of chondrocytes induced by IL-1β, decrease SELE, MMP2 and COL1 mRNA expression, likewise decrease the expression of SELE, MMP2 and COL1 protein. Conclusion: This study investigated the bioactive chemicals, crossing targets and possible mechanisms of BSHX formula against OA by network pharmacology strategy, results suggests that quercetin in BSHX formula may target on SELE, MMP2, and COL1 genes and then inhibit the progression of OA through the AGE-RAGE signaling pathway in diabetic complications. By the mechanism of reducing the apoptosis rate of SD rat chondrocytes and down-regulation the expression of genes involved in inflammation, we made sure that quercetin as principal ingredient can protect the cartilage. In addition, the conclusion of this study still need to be confirmed by in vivo and vitro experiments.

scholarly journals Homoharringtonine inhibits fibroblasts proliferation, extracellular matrix production and reduces surgery-induced knee arthrofibrosis via PI3K/AKT/mTOR pathway-mediated apoptosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yu Sun ◽  
Jihang Dai ◽  
Rui Jiao ◽  
Qing Jiang ◽  
Jingcheng Wang
Keyword(s):  
Extracellular Matrix ◽  
Cell Death ◽  
Signaling Pathway ◽  
Apoptotic Cell ◽  
Dependent Manner ◽  
Potential Mechanism ◽  
Mtor Signaling Pathway ◽  
Extracellular Matrix Production ◽  
Matrix Production

Abstract Background The prevention of surgery-induced intraarticular fibrosis remains a challenge following orthopedic surgery. Homoharringtonine (HHT) has been reported to have positive effects in preventing various kinds of fibrosis. However, little is known regarding its effect as well as the potential mechanism of HHT in preventing surgery-induced intraarticular fibrosis. Methods Various concentrations of HHTs were locally applied in vivo to reduce knee intraarticular fibrosis in rabbits. Histological macroscopic assessments such as hematoxylin and eosin (HE) staining, Masson’s trichrome staining, and Picric-sirius red polarized light were used to evaluate the effect of HHT in reducing intraarticular fibrosis. CCK-8, cell cycle assay, and EdU incorporation assay were used in vitro to detect HHT’s effect on inhibiting fibroblast viability and proliferation. The effect of HHT on fibroblast differentiation, extracellular matrix production, and apoptosis were evaluated by western blot, flow cytometry, immunofluorescent staining, and TUNEL analysis. Moreover, the expressions of PI3K/AKT/mTOR signaling pathway were detected. Results The results demonstrated that HHT could reduce the formation of intraarticular fibrosis. HHT was also found to induce fibroblast apoptotic cell death in a dose- and time-dependent manner in vitro. Moreover, HHT could effectively inhibit the production of the extracellular matrix secreted by fibroblasts and inhibited the expression of p-PI3K, p-AKT, and p-mTOR in a dose-dependent manner. After treating with insulin-like growth factor-1 (IGF-1), an activator of the PI3K/AKT axis, the expressions of pro-apoptosis-related proteins were decreased, and the fibroblast apoptosis rate was also inhibited. Conclusions In conclusion, this study demonstrated that HHT could reduce the formation of intraarticular fibrosis through the inhibition of fibroblast proliferation, extracellular matrix production, and the induction of fibroblast apoptotic cell death. Furthermore, its potential mechanism may be through the suppression of the PI3K/AKT/mTOR signaling pathway.

scholarly journals Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling

2019 ◽  
Vol 151 (8) ◽  
pp. 1051-1058 ◽  
Author(s):  
Richard Z. Lin ◽  
Zhongju Lu ◽  
Evgeny P. Anyukhovsky ◽  
Ya-Ping Jiang ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sinoatrial Node ◽  
Cardiac Pacing ◽  
Pacemaker Current ◽  
Physiological Conditions ◽  
Diastolic Depolarization ◽  
Important Regulator ◽  
Phosphoinositide 3 Kinase

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, IF, while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of IF are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.

Dapk1 promoted inflammation of infantile pneumonia by p38MAPK/NF-κB signaling pathway

2020 ◽  
Author(s):  
Wenbo Zhang
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
In Vitro Model ◽  
Potential Mechanism ◽  
Mice Model ◽  
Protein Expressions ◽  
Death Associated Protein Kinase ◽  
Vitro Model ◽  
Induction Model

Abstract Background: The present study was designed to investigate the function of Death associated protein kinase 1 (DAPK1) in infantile pneumonia and explore the potential mechanism of the actions.Methods: Male C57BL/6 mice were injected with 2 mg/kg of LPS for the mice model of infantile pneumonia. A549 cell were treated with 100 ng/ml of LPS for vitro model of infantile pneumonia. Dapk1 mRNA and protein expressions in 6, 12 or 24 h after induction model of mice.Results: Dapk1 gene increased inflammation in vitro model through activation of p38MAPK-mediated NF-κB expression. The inhibition of p38MAPK or NF-κB reduced the pro-inflammation effects of DAPK1 in infantile pneumonia.Conclusions: Our study demonstrates that Dapk1 promoted inflammation of infantile pneumonia by p38MAPK/NF-κB signaling pathway, may be achieved inflammation by activation of p38MAPK/NF-κB signaling pathway

scholarly journals Development of a Rat Model of Sick Sinus Syndrome Using Pinpoint Press Permeation

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Hong-bin Zhong ◽  
Ting-jun Wang ◽  
Gui-li Lian ◽  
Chang-sheng Xu ◽  
Hua-jun Wang ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sinoatrial Node ◽  
Sick Sinus Syndrome ◽  
Pacemaker Implantation ◽  
Time Dependent ◽  
Severely Injured ◽  
Sprague Dawley ◽  
Limited Success ◽  
Sprague Dawley Rats ◽  
Common Causes

Objective. Sick sinus syndrome (SSS) is one of the most common causes of cardiac impairment necessitating pacemaker implantation. However, studies of SSS pathogenesis are neither comprehensive nor conclusive due to limited success in achieving a stable rat SSS model. Here, we modified pinpoint press permeation to establish a stable rat SSS model. Methods. We randomly assigned 138 male Sprague-Dawley rats into three groups: normal control (n = 8), sham (n = 10), and SSS (n = 120). Postoperatively, the SSS group was further divided into SSSA (n = 40), SSSB (n = 40), and SSSC (n = 40), based on reduction in heart rates by 20–30%, 31–40%, and 41–50%, respectively. We also assessed histomorphological characteristics and hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4) expression in the sinoatrial node (SAN) at 1, 2, 3, and 4 weeks after surgery. Results. Mortality was statistically higher in SSSC compared to SSSA and SSSB (7.5% versus 90.0% and 87.5%; P < 0.05). Heart rate in SSSA was gradually restored to preoperative levels by week 4 after surgery. In contrast, heart rate in SSSB was stable at 2–3 weeks after surgery. However, we observed that the tissues and cells in SAN were severely injured and also found a time-dependent increase in collagen content and atrium myocardium in SSSB. HCN4 expression was significantly reduced at all 4 time points in SSSB, with statistically significant differences among the groups (P < 0.01). Conclusion. We successfully developed a rat SSS model that was sustainable for up to 4 weeks.

scholarly journals BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo

2014 ◽  
Vol 307 (9) ◽  
pp. H1327-H1338 ◽  
Author(s):  
Michael H. Lai ◽  
Yuejin Wu ◽  
Zhan Gao ◽  
Mark E. Anderson ◽  
Julie E. Dalziel ◽  
...  
Keyword(s):  
Heart Rate ◽  
Action Potential ◽  
Sinoatrial Node ◽  
Heart Function ◽  
Cardiac Pacing ◽  
Bk Channels ◽  
Bk Channel ◽  
Cardiac Conduction ◽  
Wild Type

Large-conductance Ca2+- and voltage-activated K+ (BK) channels play prominent roles in shaping muscle and neuronal excitability. In the cardiovascular system, BK channels promote vascular relaxation and protect against ischemic injury. Recently, inhibition of BK channels has been shown to lower heart rate in intact rodents and isolated hearts, suggesting a novel role in heart function. However, the underlying mechanism is unclear. In the present study, we recorded ECGs from mice injected with paxilline (PAX), a membrane-permeable BK channel antagonist, and examined changes in cardiac conduction. ECGs revealed a 19 ± 4% PAX-induced reduction in heart rate in wild-type but not BK channel knockout ( Kcnma1−/−) mice. The heart rate decrease was associated with slowed cardiac pacing due to elongation of the sinus interval. Action potential firing recorded from isolated sinoatrial node cells (SANCs) was reduced by 55 ± 15% and 28 ± 9% by application of PAX (3 μM) and iberiotoxin (230 nM), respectively. Furthermore, baseline firing rates from Kcnma1−/− SANCs were 33% lower than wild-type SANCs. The slowed firing upon BK current inhibition or genetic deletion was due to lengthening of the diastolic depolarization phase of the SANC action potential. Finally, BK channel immunoreactivity and PAX-sensitive currents were identified in SANCs with HCN4 expression and pacemaker current, respectively, and BK channels cloned from SANCs recapitulated similar activation as the PAX-sensitive current. Together, these data localize BK channels to SANCs and demonstrate that loss of BK current decreases SANC automaticity, consistent with slowed sinus pacing after PAX injection in vivo. Furthermore, these findings suggest BK channels are potential therapeutic targets for disorders of heart rate.

The Involvement of Platelets and the Coronary Vasculature in Collagen-Induced Sudden Death in Rabbits

1985 ◽  
Vol 53 (01) ◽  
pp. 070-074 ◽  
Author(s):  
G Mallarkey ◽  
G M Smith
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Platelet Count ◽  
Sudden Death ◽  
Myocardial Ischaemia ◽  
Plasma Levels ◽  
Sodium Citrate ◽  
Plasma Samples ◽  
Calcium Entry Blockers

SummaryThe mechanism of collagen-induced sudden death in rabbits was studied by measuring blood pressure (BP), heart rate, ECG, the continuous platelet count and the plasma levels of thromboxane B2 (TxB2) and 6-keto prostaglandin Fia (6-keto PGF1α). Death was preceded by myocardial ischaemia and a sharp fall in BP which occurred before any fall in platelet count was observed. The calcium entry blockers (CEBs), verapamil, nifedipine and PY 108-068 protected the rabbits from sudden death without any significant effect on the decrease in the platelet count or increase in plasma TxB2 levels. 6-keto PGF1α could not be detected in any plasma samples. Indomethacin and tri-sodium citrate also protected the rabbits but significantly reduced the fall in platelet count and plasma TxB2. In vitro studies on isolated aortae indicated that verapamil non-specifically inhibited vasoconstriction induced by KC1, adrenaline and U46619 (a thromboxane agonist). It is concluded that CEBs physiologically antagonize the vasoconstricting actions of platelet-derived substances and that it is coronary vasoconstriction that is primarily the cause of death.

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