Xiaoya Zhou

Naringin ameliorates metabolic syndrome by activating AMP-activated protein kinase in mice fed a high-fat diet

Metabolic syndrome is a low-grade inflammatory state in which oxidative stress is involved. Naringin, isolated from the Citrussinensis, is a phenolic compound with anti-oxidative and anti-inflammatory activities. The aim of this study was to explore the effects of naringin on metabolic syndrome in mice. The animal models, induced by high-fat diet in C57BL/6 mice, developed obesity, dyslipidemia, fatty liver, liver dysfunction and insulin resistance. These changes were attenuated by naringin. Further investigations revealed that the inhibitory effect on inflammation and insulin resistance was mediated by blocking activation of the MAPKs pathways and by activating IRS1; the lipid-lowering effect was attributed to inhibiting the synthesis way and increasing fatty acid oxidation; the hypoglycemic effect was due to the regulation of PEPCK and G6pase. The anti-oxidative stress of naringin also participated in the improvement of insulin resistance and lipogenesis. All of these depended on the AMPK activation. To confirm the results of the animal experiment, we tested primary hepatocytes exposed to high glucose system. Naringin was protective by phosphorylating AMPKα and IRS1. Taken together, these results suggested that naringin protected mice exposed to a high-fat diet from metabolic syndrome through an AMPK-dependent mechanism involving multiple types of intracellular signaling and reduction of oxidative damage.

Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats

Minocycline has been shown to protect against myocardial ischemia and reperfusion injury. However, the mechanism remains unclear. This study was to investigate the role of high mobility group box 1 protein (HMGB1) in the cardioprotection of minocycline during myocardial ischemia and reperfusion in rats. Anesthetized male rats were once treated with minocycline (45 mg/kg, i.p.) 1h before ischemia, and then subjected to ischemia for 30 min followed by reperfusion for 4h. The lactate dehydrogenase (LDH), creatine kinase (CK) and infarct size were measured and the myocardial tissue apoptosis was assessed by TUNNEL assay. Neonatal rat ventricular myocytes were prepared and then cultured with recombinant HMGB1. Cell apoptosis was measured using an annexin V-FITC apoptosis detection kit. HMGB1 expression was assessed by immunoblotting. After 4h of reperfusion, minocycline could significantly decrease the infarct size, myocardium apoptosis and the levels of LDH and CK (all P<0.05). Meanwhile, minocycline could also significantly inhibit the HMGB1 expression during myocardial ischemia and reperfusion compared to that in ischemia and reperfusion group (P<0.05). In vitro, HMGB1 could significantly decrease the cell viability and promote the apoptosis of neonatal myocytes in a dose-dependent manner. The present study suggested that minocycline could protect against myocardial ischemia and reperfusion injury by inhibiting HMGB1 expression.

Increased serum HMGB1 is related to the severity of coronary artery stenosis

BACKGROUND High mobility group box 1 (HMGB1) protein has been identified as a novel pro-inflammatory cytokine in coronary artery disease (CAD). We investigated the relationship between serum HMGB1 level and the severity of coronary artery stenosis. METHODS Serum HMGB1 concentration in patients was measured by ELISA. All patients underwent coronary angiography and were assigned into groups according to the quartile of HMGB1 level. RESULTS HMGB1 level in USAP group was higher than that in control and SAP group. HMGB1 level in SAP group was higher than that in control group (p<0.05). Gensini scores in the highest quartile group (group IV), group III and group II were all significantly higher than that in the lowest quartile group (group I). There was significant correlation between angiographic Gensini score and serum level of HMGB1 (r=0.710, p<0.05). However, in subgroup analysis, we found that serum HMGB1 level was only correlated with angiographic Gensini score in SAP patients (r=0.786, p<0.05), but not USAP patients. CONCLUSIONS Serum HMGB1 level was markedly increased with the severity of coronary artery stenosis in patients with SAP and USAP, especially in SAP patients, which suggested that increased serum HMGB1 may involve in the pathogenesis of atherosclerotic CAD.

Spinal cord stimulation protects against ventricular arrhythmias by suppressing left stellate ganglion neural activity in an acute myocardial infarction canine model.

BACKGROUND Previous studies have shown that spinal cord stimulation (SCS) may reduce ventricular arrhythmias (VAs) induced by acute myocardial infarction (AMI). Furthermore, activation of left stellate ganglion (LSG) appears to facilitate VAs after AMI. OBJECTIVE The purpose of this study was to investigate whether pretreatment with SCS could protect against VAs by reducing LSG neural activity in an AMI canine model. METHODS Thirty dogs were anesthetized and randomly divided into SCS group (with SCS, n = 15) and sham group (sham operation without SCS, n = 15). SCS was performed for 1 hour before AMI. Heart rate variability (HRV), ventricular effective refractory period (ERP), serum norepinephrine level, LSG function measured by blood pressure increases in response to LSG stimulation, and LSG neural activity were measured for 1 minute at baseline and 1 hour after SCS. AMI was induced by left anterior descending coronary artery ligation, and then HRV, LSG neural activity, and VAs were measured. RESULTS Compared to baseline, SCS for 1 hour significantly prolonged ventricular ERP, increased HRV, and attenuated LSG function and LSG activity in the SCS group, whereas no significant change was shown in the sham group. AMI resulted in a significant decrease in HRV and increase in LSG neural activity in the sham group, which were attenuated in the SCS group (frequency: 99 ± 34 impulses/min vs 62 ± 22 impulses/min; amplitude: 0.41 ± 0.12 mV vs 0.18 ± 0.05 mV; both P <.05). The incidence of VAs was significantly lower in the SCS group than in the sham group. CONCLUSION SCS may prevent AMI-induced VAs, possibly by suppressing LSG activity.

Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling

BACKGROUND Previous study has shown that spinal cord stimulation (SCS) may suppress atrial fibrillation (AF) inducibility, but the mechanism for this is elusive. OBJECTIVE The purpose of this study was to determine whether SCS could inhibit AF inducibility by suppressing autonomic remodeling in a canine model of rapid atrial pacing (RAP)-induced AF. METHODS Eighteen canines were randomly divided into an RAP group (n = 9) and an RAP+SCS group (n = 9). Effective refractory period (ERP), window of vulnerability (WOV), AF inducibility, autonomic neural function, and activity from the anterior right ganglionated plexus (ARGP) and left stellate ganglion (LSG) were measured at baseline, at 3 hours of RAP, and at 6 hours of RAP. Then, ARGP and LSG were excised for Western blot and messenger RNA analysis. In another 4 dogs (control group, which received sham RAP and sham SCS), tissues were also excised for analysis. RESULTS In the RAP group, RAP resulted in (1) a significant decrease in ERP and an increase in ERP dispersion, ΣWOV, and AF inducibility and (2) activation of ARGP and LSG versus baseline. In the RAP+SCS group, however, these changes were significantly attenuated by SCS. Compared with the control group, c-fos and nerve growth factor (NGF) were significantly up-regulated and small conductance calcium-activated potassium channel type 2 (SK2) was significantly down-regulated in the RAP group. In the RAP+SCS group, however, c-fos, NGF, and SK2 remained at a normal level compared with the control group. CONCLUSION SCS may suppress RAP-induced AF by inhibiting autonomic remodeling, and the underlying mechanism of the salutary effect of SCS might contribute to modulation of the expression of c-fos, NGF, and SK2.

Exogenous High-Mobility Group Box 1 Protein Injection Improves Cardiac Function after Myocardial Infarction: Involvement of Wnt Signaling Activation

Exogenous high-mobility group box 1 protein (HMGB1) injection could prevent left ventricular remodeling and enhance left ventricular function during myocardial infarction (MI). However, the mechanism remains unclear. This paper was to investigate in the mechanism of cardioprotection of HMGB1 during MI in rats. Anesthetized male rats were treated once with HMGB1 (200 ng) 4 h after MI and then executed after 7 and 28 days, respectively. Cardiac function, collagen deposition, and dishevelled-1 and β-catenin protein expression were measured. After MI 7 days or 28 days, the left ventricular ejection fraction (LVEF) was significantly decreased compared to that of sham-operated control group (P < 0.05). However, the LVEF HMGB1-treated groups were significantly higher compared to those of the MI group in both 7 days and 28 days (P < 0.05). The collagen volume fraction was significantly reduced in the HMGB1-treated group in infarcted border zone. HMGB1 could activate the expression of dishevelled-1 and β-catenin proteins (P < 0.05). Our study suggested that exogenous high-mobility group box 1 protein injection improves cardiac function after MI, which may be involved in Wnt/β-catenin signaling activation.

Carotid baroreceptor stimulation prevents arrhythmias induced by acute myocardial infarction through autonomic modulation.

Abstract: Electrical carotid baroreceptor stimulation (CBS) has shown therapeutic potential for resistant hypertension and heart failure by resetting autonomic nervous system, but the impacts on arrhythmias remains unclear. This study evaluated the effects of CBS on ventricular electrophysiological properties in normal dog heart and arrhythmias after acute myocardial infarction (AMI). In the acute protocol, anesthetized open chest dogs were exposed to 1 hour left anterior descending coronary occlusion as AMI model. Dogs were received either sham treatment (Control group, n = 8) or CBS (CBS group, n = 8), started 1 hour before AMI. CBS resulted in pronounced prolongation of ventricular effective refractory period and reduction of the maximum action potential duration restitution slope (from 0.85 ± 0.15 in the baseline state to 0.67 ± 0.09 at the end of 1 hour, P < 0.05) before AMI. Number of premature ventricular contractions (277 ± 168 in the Control group vs. 103 ± 84 in the CBS group, P < 0.05) and episodes of ventricular tachycardia/ventricular fibrillation (7 ± 3 in the Control group vs. 3 ± 2 in the CBS group, P < 0.05) was decreased compared with the control group during AMI. CBS buffered low-frequency/high-frequency ratio raise during AMI. Ischemic size was not affected by CBS. CBS may have a beneficial impact on ventricular arrhythmias induced by AMI through modulation of autonomic tone.

Exogenous high-mobility group box 1 protein prevents postinfarction adverse myocardial remodeling through TGF-β/Smad signaling pathway.

High‐mobility group box 1 (HMGB1) has been reported to attenuate ventricular remodeling, but its mechanism remains mostly unresolved. Transforming growth factor‐beta (TGF‐β) is a crucial mediator in the pathogenesis of post‐infarction remodeling. Our study focused on the effects of HMGB1 on ventricular remodeling, and explored whether or not these effects were depended upon the TGF‐β signaling pathway. Rats underwent coronary artery ligation. An intramyocardium injection of phosphate buffered saline (PBS) with or without HMGB1 was administered 3 weeks after myocardial infarction (MI). At 4 weeks after the treatment, HMGB1 significantly increased the left ventricular ejection fraction (LVEF) (P < 0.05), decreased the left ventricular end diastolic dimension (LVEDD; P < 0.05), left ventricular end systolic dimension (LVESD) (P < 0.05) and the infarct size (P < 0.05) compared with control group. The expressions of collagen I, collagen III, and tissue inhibitor of metalloproteinase 2 (TIMP2) were also decreased, while the matrix metalloproteinases 2 (MMP2) and MMP9 expressions were upregulated by HMGB1 injection (P < 0.05) compared with control group. No effect on TIMP3 was observed. Furthermore, TGF‐β1 and phosphor‐Smad2 (p‐Smad2) were significantly suppressed and Smad7 was increased in HMGB1‐treated group (P < 0.05) compared with control group, no effects on p‐Smad3 and p‐p38 were observed. HMGB1 also upregulated Smad 7 expression and decreased the level of collagen I on cardiac fibroblasts (P < 0.05). Silencing of Smad7 gene by small interfering RNA abolished the fibrogenic effects of HMGB1 on cardiac fibroblasts (P < 0.05). These finding suggested that HMGB1 injection modulated ventricular remodeling may function through the possible inhibition of TGF‐β/Smad signaling pathway. J. Cell. Biochem. 114: 1634–1641, 2013.

Low level non-invasive vagus nerve stimulation: A novel feasible therapeutic approach for atrial fibrillation

1. Autonomic nervous system and arrhythmiasThe autonomic nervous system plays an important role in the mod-ulation of cardiac arrhythmogenesis, and autonomic nerve activity canact as a direct trigger of arrhythmias. In atrial fibrillation, sympatheticleft stellate ganglion (LSG) and atrial ganglionated plexus activations(GP) are the most common trigger [1].2. Anti-atrial fibrillation effects induced by low-level vagus nervestimulation (LL-VNS)Inpreviousstudies,wefoundthatlow-levelvagusnervestimulation(LL-VNS), at voltages substantially below that which slowed the sinusrate significantly increases the effective refractory period (ERP) in theatria as well as the pulmonary vein (PV) myocardium. Furthermore,AFinducibilityatthesesiteswassignificantlysuppressedandtheAFdu-rationwassubstantiallyshortenedaswell.Directneuralrecordingsalsoindicatethattheanti-arrhythmiceffectsofLL-VNSaremediatedbysup-pressingtheactivityofGP[2–5].Shenetal.alsodemonstratedthatcon-tinuous LL-VNS suppressed paroxysmal atrial tachyarrhythmias inambulatory, conscious dogs via the reduction of stellate ganglionnerve activity. Histologically, LL-VNS resulted in a significant reductionof sympathetic ganglion cells in the LSG [1].3. Beneficial effects of non-invasive LL-VNSOur recent study reported a noninvasive anti-arrhythmic ap-proach to deliver VNS by transcutaneous stimulation at the tragus,where the auricular branch of the vagus nerve is located. Non-invasive LL-VNS can reverse RAP-induced atrial remodeling and in-hibit AF inducibility, suggesting a potential non-invasive treatmentfor AF [6,7].Vagus nerve stimulation (VNS) is currently used to treat refractoryepilepsy and is being investigated as a potential therapy for a range ofconditions, includingventricularfibrillation,heart failure, tinnitus,obe-sity and Alzheimers disease. However, the invasive nature (the VNSneurostimulator system has to be implanted by surgery and maycause some side effects, such as neck pain, coughing, swallowing diffi-culty, and voice alteration along with nausea and indigestion) and ex-pense limit the use of VNS in patient populations [8–11].Although, multiple experiment and clinical studies demonstratedthat ablation of targeted neural elements reduced the incidences of ar-rhythmias. Ablation approach has also multiple limitations. One limita-tionisthattheautonomicnervoussystemishighlyplastic.It ispossiblethat reinnervation can occur after the ablation procedures and negatetheeffectsofablation.Asecondlimitationisthattheatrialganglionatedplexusand stellateganglionare noteasily accessiblein humans. Athirdlimitation is that ablation of the ganglion causes irreversible changes oftheautonomicnervoussystem.Thelong-termeffectsofautonomicner-vous system denervation in patients with arrthymia are still unknown.Because of the above limitations, it is highly desirable to develop aneuromodulation method that can be easily terminated, without caus-ing permanent damage to the autonomic structures.We examined the effects of a noninvasive therapeutic modality tosubstitute for vagus nerve stimulation. We therefore propose a newneural interface approach to optimize cardiac autonomic tone. Thesedistinguishing features that underlie the potential clinical significanceof this therapeutic approach provide us a novel, noninvasive approachto treat arrhythmias. Notably, non-invasive LL-VNS exerted powerfulanti-arrhythmiceffectswhendeliveredtoeachanimalatasubstantiallylow voltage (80% below the threshold of slowing sinus rate). This ap-proach is potentially tolerable by ambulatory patients. A very recentclinical study alsoshowed that non-invasive LL-VNS in healthyhumansreduced sympathetic nerve activity [12]. Non-invasive LL-VNS cantherefore influence human physiology and provide a simple and inex-pensive alternative to invasive VNS.

Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor β1.

Abstract: Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor &bgr;1 (TGF-&bgr;1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-&bgr;1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-&bgr;1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-&bgr;1 expression.