Abstract Background Autophagy serves as a cellular protective mechanism against alcohol induced tissue injury but excessive autophagy can also be detrimental leading to apoptosis. Our lab has ...previously shown that moderate alcohol consumption alters expression of proteins in the insulin signaling pathway and worsens glucose metabolism in the liver in a swine model of metabolic syndrome. We examined the effect of alcohol consumption on apoptosis and autophagy signaling in the liver in our clinically relevant animal model of chronic hypercholesterolemia. Materials Twenty-six Yorkshire swine were fed a high fat diet for 4 weeks then split into 3 groups: hypercholesterolemic diet alone (HCC, n= 9), hypercholesterolemic diet with vodka (HCV, n= 9), and hypercholesterolemic diet with wine (HCW, n = 8) for 7 weeks. Animals underwent euthanasia and liver tissue samples were harvested for analysis. Methods Liver tissue was analyzed via western blot analysis. Protein density data was normalized to GAPDH and is reported as fold change values+/- SEM compared to the high cholesterol diet control group. A Kruskal Wallis test with a Dunn’s multiple comparison test was used to compare the means among groups. Results The HCVgroup showed significant increases in several pro apoptotic proteins (including caspase 3, caspase 8, caspase 9 and cleaved caspase 9) compared to the HCC group. There was a decrease in the pro apoptotic protein (BAD) and an increase in anti-apoptotic signal (BCL-2) in the HCW group compared to HCC control. There were increases in pro-survival proteins (AKT, p-AKT, mTOR, p-mTOR) in the HCW and the HCV group compared to control (HCC). There were decreases in autophagy protein LCB-3 in the HCW and HCV compared to the control. Conclusions We found that moderate alcohol consumption altered protein expression related to apoptosis and autophagy signaling in pig liver in the setting of hypercholesterolemia. Interestingly, vodka may induce pro-apoptotic pathways in liver tissue, whereas wine may induce anti apoptotic signaling. These results provide a mechanism by which vodka may contribute to alcoholic liver disease and supports the notion that wine, containing resveratrol, may prevent cellular apoptosis in liver tissue in the setting of hypercholesterolemia.
Background
Inhibition of glycogen synthase kinase 3β (GSK‐3β) has been reported to be cardioprotective during stressful conditions.
Methods and Results
Pigs were fed a high‐fat diet for 4 weeks to ...develop metabolic syndrome, then underwent placement of an ameroid constrictor to their left circumflex artery to induce chronic myocardial ischemia. Two weeks later, animals received either: no drug (high cholesterol control group HCC) or a GSK‐3β inhibitor (GSK‐3β inhibited group GSK‐3βI), which were continued for 5 weeks, followed by myocardial tissue harvest. Coronary blood flow and vessel density were significantly increased in the GSK‐3βI group compared to the HCC group. Expression levels of the following proteins were greater in the GSK‐3βI group compared to the HCC group: vascular endothelial growth factor receptor 1 , vascular endothelial cadherin, γ‐catenin, β‐catenin, protein kinase B, phosphorylated forkhead box O1, and superoxide dismutase 2.
Conclusions
In the setting of metabolic syndrome, inhibition of GSK‐3β increases blood flow and vessel density in chronically ischemic myocardium. We identified several angiogenic, cell survival, and differentiation pathways that include β‐catenin signaling and AKT/FOXO1, through which GSK‐3β appears to improve vessel density and blood flow. These results may provide a potential mechanism for medical therapy of patients suffering from coronary artery disease and metabolic syndrome.
Cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally ...identified as a delta-protein kinase C inhibitor, has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin mitigates deleterious effects associated with CP/CPB.
Langendorff-perfused isolated rat hearts were subjected to 2 hours intermittent cold (10°C) CP (St Thomas II) followed by 30 minutes normothermic reperfusion. CP was delivered every 30 minutes for 1 minute. Hearts were treated with rottlerin 1 μmol/L (CP+R) (n=7) or without rottlerin (CP) (n=9), and the BK(Ca++) channel inhibitor paxilline 100 nmol/L was supplied in the CP. Hearts constantly perfused with KHB served as controls (n=6). Baseline parameters of cardiac function were similar between groups. CP resulted in reduced cardiac function (left ventricular diastolic pressure, 39 ± 3.8%; ± dP/dt, 32 ± 4.4%, -41 ± 5.1% decrease compared to baseline). Treatment with rottlerin 1 μmol/L significantly improved CP-induced cardiac function (left ventricular diastolic pressure, 20 ± 5.9%; ± dP/dt, 5.2 ± 4.5%, -11.6 ± 4.7% decrease versus baseline; P<0.05 CP+R versus CP). Rottlerin also caused a significant increase in coronary flow postreperfusion (CP, 34 ± 4.2% decrease from baseline; CP+R, 26 ± 9.6% increase over baseline; P=0.01). Independent of vascular effects, CP significantly decreased isolated myocyte contraction, which was restored by rottlerin treatment. The BK(Ca++) channel inhibitor greatly reduced the majority of beneficial effects associated with rottlerin.
Rottlerin significantly improves cardiac performance after CP arrest through improved cardiomyocyte contraction and coronary perfusion.
Neuronal plasticity contributes to postictal death Brodovskaya, Anastasia; Sun, Huayu; Adotevi, Nadia ...
Progress in neurobiology,
December 2023, 2023-Dec, 2023-12-00, 20231201, Letnik:
231
Journal Article
Recenzirano
Repeated generalized tonic-clonic seizures (GTCSs) are the most critical risk factor for sudden unexpected death in epilepsy (SUDEP). GTCSs can cause fatal apnea. We investigated neuronal plasticity ...mechanisms that precipitate postictal apnea and seizure-induced death. Repeated seizures worsened behavior, precipitated apnea, and enlarged active neuronal circuits, recruiting more neurons in such brainstem nuclei as periaqueductal gray (PAG) and dorsal raphe, indicative of brainstem plasticity. Seizure-activated neurons are more excitable and have enhanced AMPA-mediated excitatory transmission after a seizure. Global deletion of the GluA1 subunit of AMPA receptors abolishes postictal apnea and seizure-induced death. Treatment with a drug that blocks Ca2+-permeable AMPA receptors also renders mice apnea-free with five-fold better survival than untreated mice. Repeated seizures traffic the GluA1 subunit-containing AMPA receptors to synapses, and blocking this mechanism decreases the probability of postictal apnea and seizure-induced death.
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•Repeated generalized seizures are the most significant risk factor for SUDEP.•Repeated mouse seizures led to apnea, death, and larger activated neuronal network.•Activated neurons had enhanced, Ca2 + permeable, AMPA receptor-mediated transmission.•Global deletion of the AMPAR GluA1 subunit abolished seizure-induced apnea and death.•Drug blockade of Ca2 + -permeable AMPARs reduced apnea and death.
Background Resveratrol has been reported to induce angiogenesis in ischemic tissue. We hypothesized that high-dose resveratrol would improve native angiogenesis in a swine model of metabolic syndrome ...and chronic myocardial ischemia. Methods Yorkshire swine were fed a normal diet (Control, n = 7), hypercholesterolemic diet (HCD, n = 7), or hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/day orally, HCD-R; n = 7) beginning 1 month prior to surgery. Chronic ischemia was created by placing an ameroid constrictor on the left circumflex coronary artery. After 7 weeks, swine underwent functional MRI, coronary angiography, and serum and heart tissue harvest for analysis. Results HCD-R animals had lower body mass index ( P < .001), total cholesterol ( P < .001), low-density lipoprotein (LDL; P < .001), blood glucose levels ( P < .001), and systolic blood pressure ( P = .03) than HCD animals. There was no difference in regional myocardial function at 7 weeks ( P = .25). Coronary angiograms revealed no difference in Rentrop collateral scores ( P = .68). Staining for platelet endothelial cell adhesion molecule-1 demonstrated higher capillary density in the Control group (versus HCD and HCD-R; P = .02). Immunoblotting demonstrated decreased expression of the pro-angiogenic protein vascular endothelial (VE)-cadherin ( P = .002) and an increase in anti-angiogenic proteins angiostatin ( P = .001) and thrombospondin ( P = .02) in the HCD and HCD-R groups. Matrix metalloprotease 2 (MMP 2; P = .47) and MMP 9 ( P = .12) were not different among groups. Conclusion Supplemental resveratrol positively modified cardiovascular risk factors including body mass index, cholesterol, glucose tolerance, and systolic blood pressure. However, it did not increase native collateral formation in the ischemic myocardium. This may be a result of increased angiostatin and thrombospondin leading to decreased expression of VE-cadherin and other pro-angiogenic factors.
Network effects may be either direct or indirect. While many analyses conflate the two, I show that the ways in which direct and indirect effects influence technological standardization are quite ...different. Some parameter changes have opposite effects in the two models, and some factors which are irrelevant under direct effects are central under indirect effects. Compatibility in particular has a different interpretation and more subtle implications for standardization in the indirect model.
Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting ...pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling.
PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON-normoxic animals with placebo (n=18); PH-Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16).
In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone.
Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.
Background Clinical trials of therapeutic angiogenesis with vascular endothelial growth factor (VEGF) have been disappointing, owing likely to endothelial dysfunction. We used a swine model of ...chronic ischemia and endothelial dysfunction to determine whether resveratrol coadministration would improve the angiogenic response to VEGF therapy. Methods Yorkshire swine fed a high-cholesterol diet underwent left circumflex ameroid constrictor placement, and were given either no drug (high cholesterol control HCC, n = 8), perivascular VEGF (2 μg sustained release high cholesterol VEGF-treated; HCV, n = 8), or VEGF plus oral resveratrol (10 mg/kg, high cholesterol VEGF- and resveratrol-treated; HCVR, n = 8). After 7 weeks, myocardial contractility, perfusion, and microvessel reactivity in the ischemic territory were assessed. Tissue was analyzed for vessel density, oxidative stress, and protein expression. Results Myocardial perfusion was significantly improved in the HCV group compared with the HCC group; resveratrol coadministration abrogated this improvement. There were no differences in regional myocardial contractility between groups. Endothelium-dependent microvessel relaxation was improved in the HCVR group, and endothelium-independent relaxation response was similar between groups. Arteriolar density was greatest in the HCV group, whereas capillary density was similar between groups. Expression of Akt and phospho-endothelial nitric oxide synthase were increased in the HCVR group. Total protein oxidative stress and myeloperoxidase expression were reduced in the HCVR group, but so was the oxidative-stress dependent phosphorylation of vascular endothelial cadherin (VE-cadherin) and β-catenin. Conclusion Although resveratrol coadministration decreases oxidative stress and improves endothelial function, it abolishes improvements in myocardial perfusion and arteriolar density afforded by VEGF treatment alone. This effect is due likely to inhibition of the oxidative stress-dependent phosphorylation of VE-cadherin, an essential step in the initiation of arteriogenesis.
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