- Pathophysiological roles of canstatin on myofibroblasts after myocardial infarction in rats. [Journal Article]
- EJEur J Pharmacol 2017 Apr 21
- Myofibroblasts play an important role during remodeling process after myocardial infarction through proliferation, migration, production and degradation of extracellular matrix and contraction. Canst...
Myofibroblasts play an important role during remodeling process after myocardial infarction through proliferation, migration, production and degradation of extracellular matrix and contraction. Canstatin, a 24kDa polypeptide, is cleaved from α2 chain of type IV collagen, which is a major component of basement membrane around cardiomyocytes. We examined the effects of canstatin on myofibroblasts isolated from the areas of myocardial infarction. Myocardial infarction model was made by ligating left anterior descending artery of Wistar rats. Two weeks after the operation, the cells were isolated by an explant method and identified as myofibroblasts with immunofluorescence staining. Cell counting assay was performed to examine cell proliferation. Boyden chamber assay was performed to examine cell migration. Expression and phosphorylation of proteins were detected by Western blotting. Collagen gel contraction assay was performed to measure cell contractility. Canstatin stimulated proliferation, secretion of matrix metalloproteinases (MMPs), expression of cyclooxygenase-2, and inhibited collagen gel contraction in myofibroblasts. Canstatin increased Akt phosphorylation. LY294002, a phosphoinositide-3-kinase/Akt inhibitor, inhibited the canstatin-induced proliferation. NS-398, a COX-2 inhibitor, suppressed the inhibitory effect of canstatin on collagen gel contraction. Canstatin expression in areas of myocardial infarction 2 weeks after surgery decreased. We for the first time demonstrate that canstatin is an endogenous bioactive molecule regulating the various functions of myofibroblasts after myocardial infarction. The decrease of canstatin expression in the maturated areas of myocardial infarction might lead to stabilization of scar tissues perhaps in part through the reduction of proliferation and ECM degradation as well as the stimulation of contractility in myofibroblasts.
- The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy. [Journal Article]
- EJEur J Pharmacol 2017 Apr 21
- Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions...
Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47(phox)), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.
- Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents. [Journal Article]
- EJEur J Pharmacol 2017 Apr 21
- The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine rece...
The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483.
- Diammonium glycyrrhizinate alleviates hepatopulmonary syndrome via restoring superoxide dismutase 3 activity in rats. [Journal Article]
- EJEur J Pharmacol 2017 Apr 20
- Hepatopulmonary syndrome (HPS) has a fatal hypoxemia from pulmonary shunts. Superoxide dismutase 3 (SOD3) deficiency involves in this pathogenesis. The purpose of this study was to investigate the un...
Hepatopulmonary syndrome (HPS) has a fatal hypoxemia from pulmonary shunts. Superoxide dismutase 3 (SOD3) deficiency involves in this pathogenesis. The purpose of this study was to investigate the underlying mechanisms of diammonium glycyrrhizinate (DG) on HPS via SOD3. Carbon tetrachloride induced HPS rats were treated with captopril or DG for 56 days. Blood gas, pulmonary artery pressures, and histological changes were measured. Molecule dynamics of inducible (iNOS), endothelial (eNOS), neuronal nitric oxide synthase (nNOS) and SOD3 were assessed by immunohistochemistry, quantitative RT-PCR and western blot. The results showed that DG significantly increased partial pressure of oxygen (P<0.01), decreased alveolar-arterial oxygen gradient (P<0.01), and improved hypoxemia. In HPS model rats, anatomical pulmonary shunts were demonstrated as both constricted arterioles and dilated metarterioles, while physiological shunts were demonstrated by lowered pulmonary artery pressure in vivo. DG significantly reversed the vascular pathological changes. Elevated iNOS or eNOS, and decreased SOD3 expression in model rats indicated imbalance of nitric oxide (NO) bioavailability. Partial SOD3 potencies correlated with circulative events and NOSs, indicating that restorable SOD3 regulated arteriole constriction and metarteriole dilatation. DG reduced iNOS or eNOS, increased SOD3 expression, especially significantly increased the partial SOD3 located in pulmonary arteries (P<0.05), arterioles (P<0.05) and alveolus (P<0.05). These results suggested that DG relieved HPS shunts and limited HPS pathogenesis may associate with restoring SOD3 activity.
- Plaque angiogenesis and intraplaque hemorrhage in atherosclerosis. [Journal Article]
- EJEur J Pharmacol 2017 Apr 21
- Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence suggests that plaque neovascula...
Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence suggests that plaque neovascularization is an important contributor to plaque growth and instability. The vessels' immaturity, with profound structural and functional abnormalities, leads to recurrent intraplaque hemorrhage. This review discusses new insights of atherosclerotic neovascularization, including the effects of leaky neovessels on intraplaque hemorrhage, both in experimental models and humans. Furthermore, modalities for in vivo imaging and therapeutic interventions to target plaque angiogenesis will be discussed.
- (-)-Terpinen-4-ol changes intracellular Ca(2+) handling and induces pacing disturbance in rat hearts. [Journal Article]
- EJEur J Pharmacol 2017 Apr 20
- (-)-Terpinen-4-ol is a naturally occurring plant monoterpene and has been shown to have a plethora of biological activities. The objective of this study was to investigate the effects of (-)-terpinen...
(-)-Terpinen-4-ol is a naturally occurring plant monoterpene and has been shown to have a plethora of biological activities. The objective of this study was to investigate the effects of (-)-terpinen-4-ol on the rat heart, a key player in the control and maintenance of arterial blood pressure. The effects of (-)-terpinen-4-ol on the rat heart were investigated using isolated left atrium isometric force measurements, in vivo electrocardiogram (ECG) recordings, patch clamp technique, and confocal microscopy. It was observed that (-)-terpinen-4-ol reduced contraction force in an isolated left atrium at millimolar concentrations. Conversely, it induced a positive inotropic effect and extrasystoles at micromolar concentrations, suggesting that (-)-terpinen-4-ol may have arrhythmogenic activity on cardiac tissue. In anaesthetized animals, (-)-terpinen-4-ol also elicited rhythm disturbance, such as supraventricular tachycardia and atrioventricular block. To investigate the cellular mechanism underlying the dual effect of (-)-terpinen-4-ol on heart muscle, experiments were performed on isolated ventricular cardiomyocytes to determine the effect of (-)-terpinen-4-ol on L-type Ca(2+) currents, Ca(2+) sparks, and Ca(2+) transients. The arrhythmogenic activity of (-)-terpinen-4-ol in vitro and in vivo may be explained by its effect on intracellular Ca(2+) handling. Taken together, our data suggest that (-)-terpinen-4-ol has cardiac arrhythmogenic activity.
- miR-938 promotes colorectal cancer cell proliferation via targeting tumor suppressor PHLPP2. [Journal Article]
- EJEur J Pharmacol 2017 Apr 19
- Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although the development of therapy approaches, the outcome of CRC patients still is poor, understanding the b...
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although the development of therapy approaches, the outcome of CRC patients still is poor, understanding the biological mechanism of CRC progression is critical to improve the treatment strategies. miRNAs regulate CRC progression, we found miR-938 was upregulated in CRC tissues and cells, MTT assay, colony formation assay and soft agar growth assay suggested miR-938 overexpression promoted CRC cell proliferation, miR-938 knockdown inhibited CRC cell proliferation. Tumor suppressor PH domain Leucine-rich-repeats Protein Phosphatase 2 (PHLPP2) was a target of miR-938, miR-938 inhibited PHLPP2, luciferase activity assay suggested miR-938 directly bound to the 3'UTR of PHLPP2, meanwhile, we found miR-938 promoted c-Myc and Cyclin D1 expression, confirming miR-938 promoted CRC cell proliferation. Double knockdown of miR-938 and PHLPP2 promoted CRC cell proliferation, suggesting miR-938 promoted CRC cell proliferation by inhibiting PHLPP2.
- Impaired endothelium-derived hyperpolarization-type relaxation in superior mesenteric arteries isolated from female Otsuka Long-Evans Tokushima Fatty rats. [Journal Article]
- EJEur J Pharmacol 2017 Apr 19
- Endothelium-derived hyperpolarization (EDH) is an important signaling mechanism of endothelium-dependent vasorelaxation, and little attention has been paid to the EDH-type responses in female metabol...
Endothelium-derived hyperpolarization (EDH) is an important signaling mechanism of endothelium-dependent vasorelaxation, and little attention has been paid to the EDH-type responses in female metabolic syndrome such as that observed with type-2 diabetes. We previously reported that EDH-type relaxation was impaired in superior mesenteric arteries from male Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type-2 diabetes, however, the response was unclear in female OLETF rat. Thus, the aim of this study was to examine if EDH-type relaxation was altered in superior mesenteric arteries isolated from female OLETF rats compared to age-matched, control female Long-Evans Tokushima Otsuka (LETO) rats at age 50-59 weeks. We investigated concentration-relaxation curves for acetylcholine (at age 50-53 weeks), NS309 (an activator of small- and intermediate-conductance calcium-activated potassium channels) (at age 50-53 weeks), and GSK1016790A (an agonist of transient receptor potential vanilloid type 4, TRPV4) (at age 58 or 59 weeks) in the presence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine and the cyclooxygenase inhibitor indomethacin to investigate EDH-type responses in the superior mesenteric artery. Obesity, mild hyperglycemia, hyperinsulinemia, and hyperlipidemia (i.e., increased total cholesterol, triglyceride, and non-esterified fatty acids) were more frequent in OLETF rats than in age-matched LETO rats at age 50-53 weeks. Acetylcholine-, NS309-, and GSK1016790A-induced relaxations in arteries from OLETF rats were all significantly reduced compared to those in LETO rats. These results indicated that EDH-type relaxations were impaired in female OLETF rats. This novel experimental model may provide new insights into vascular dysfunction in metabolic syndrome in females.
- Force development and intracellular Ca(2+) in intact cardiac muscles from gravin mutant mice. [Journal Article]
- EJEur J Pharmacol 2017 Apr 17
- Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β2-adrenergic receptor (β2-AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β2-AR-dependent...
Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β2-adrenergic receptor (β2-AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β2-AR-dependent signal transduction through PKA to modulate cardiac excitation-contraction coupling and its removal positively affects cardiac contraction. Trabeculae from the right ventricles of gravin mutant (gravin-t/t) mice were employed for force determination. Simultaneously, corresponding intracellular Ca(2+) transient ([Ca(2+)]i) were measured. Twitch force (Tf)-interval relationship, [Ca(2+)]i-interval relationship, and the rate of decay of post-extrasysolic potentiation (Rf) were also obtained. Western blot analysis were performed to correlate sarcomeric protein expression with alterations in calcium cycling between the WT and gravin-t/t hearts. Gravin-t/t muscles had similar developed force compared to WT muscles despite having lower [Ca(2+)]i at any given external Ca(2+) concentration ([Ca(2+)]o). The time to peak force and peak [Ca(2+)]i were slower and the time to 75% relaxation was significantly prolonged in gravin-t/t muscles. Both Tf-interval and [Ca(2+)]i-interval relations were depressed in gravin-t/t muscles. Rf, however, did not change. Furthermore, Western blot analysis revealed decreased ryanodine receptor (RyR2) phosphorylation in gravin-t/t hearts. Gravin-t/t cardiac muscle exhibits increased force development in responsiveness to Ca(2+). The Ca(2+) cycling across the SR appears to be unaltered in gravin-t/t muscle. Our study suggests that gravin is an important component of cardiac contraction regulation via increasing myofilament sensitivity to calcium. Further elucidation of the mechanism can provide insights to role of gravin if any in the pathophysiology of impaired contractility.
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- Inhibitory effects of losartan and azelnidipine on augmentation of blood pressure variability induced by angiotensin II in rats. [Journal Article]
- EJEur J Pharmacol 2017 Apr 15
- Increased blood pressure variability has been shown to be associated with cardiovascular morbidity and mortality. Recently we reported that continuous infusion of angiotensin II not only elevated blo...
Increased blood pressure variability has been shown to be associated with cardiovascular morbidity and mortality. Recently we reported that continuous infusion of angiotensin II not only elevated blood pressure level, but also increased blood pressure variability in a manner assumed to be independent of blood pressure elevation in rats. In the present study, the effects of the angiotensin type I receptor blocker losartan and the calcium channel blocker azelnidipine on angiotensin II-induced blood pressure variability were examined and compared with that of the vasodilator hydralazine in rats. Nine-week-old male Wistar rats were subcutaneously infused with 240 pmol/kg/min angiotensin II for two weeks without or with oral administration of losartan, azelnidipine, or hydralazine. Blood pressure variability was evaluated using a coefficient of variation of blood pressure recorded every 15min under an unrestrained condition via an abdominal aortic catheter by a radiotelemetry system. Treatment with losartan suppressed both blood pressure elevation and augmentation of systolic blood pressure variability in rats infused with angiotensin II at 7 and 14 days. Azelnidipine also inhibited angiotensin II-induced blood pressure elevation and augmentation of blood pressure variability; meanwhile, hydralazine attenuated the pressor effect of angiotensin II, but had no effect on blood pressure variability. In conclusion, angiotensin II augmented blood pressure variability in an angiotensin type 1 receptor-dependent manner, and azelnidipine suppressed angiotensin II-induced augmentation of blood pressure variability, an effect mediated by the mechanism independent of the blood pressure-lowering action.