Abstract:
PURPOSE:This study tested if the protective anti-remodeling effect of GLP-1 agonist Exendin-4 after an acute myocardial infarction (MI) in rats involves inhibition of the Wnt1/β-catenin signaling pathway. METHODS:Rats were divided into sham, sham + Exendin-4 (10 μg/day, i.p), MI, and MI + Exendin-4. MI was introduced to rats by permanent left anterior descending coronary artery (LAD) ligation. RESULTS:On day 7 post-infraction, MI rats showed LV dysfunction with higher serum levels of cardiac markers. Their remote myocardia showed increased mRNA and protein levels of collagen I/III with higher levels of reactive oxygen species (ROS) and inflammatory cytokines, as well as protein levels of Wnt1, phospho-Akt, transforming growth factor (TGF-β1), Smad, phospho-Smad3, α-SMA, caspase-3, and Bax. They also showed higher protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β), as well as total, phosphorylated, and nuclear β-catenin with a concomitant decrease in the levels of cyclic adenosine monophosphate (cAMP), mRNA of manganese superoxide dismutase (MnSOD), and protein levels of Bcl-2, β-arrestin-2, and protein phosphatase-2 (PP2A). Administration of Exendin-4 to MI rats reduced the infarct size and reversed the aforementioned signaling molecules without altering protein levels of TGF-1β and Wnt1 or Akt activation. Interestingly, Exendin-4 increased mRNA levels of MnSOD, protein levels of β-arrestin-2 and PP2A, and β-catenin phosphorylation but reduced the phosphorylation of GSK3β and Smad3, and total β-catenin levels in the LV of control rats. CONCLUSION:Exendin-4 inhibits the remodeling in the remote myocardium of rats following acute MI by attenuating β-catenin activation and activating β-arrestin-2, PP2A, and GSK3β. Graphical Abstract A graphical abstract that illustrates the mechanisms by which Exendin-4 inhibits cardiac remodeling in remote myocardium of left ventricle MI-induced rats. Mechanisms are assumed to occur in the cardiomyocytes and/or other resident cells such as fibroblast. Β-catenin activation and nuclear translocation are associated with increased synthesis of inflammatory cytokines and transforming growth factor β-1 (TGF-β1). GSK3β is inhibited by phosphorylation at Ser9. Under normal conditions, β-catenin is degraded in the cytoplasm by the active GSK3β-dependent degradation complex (un-phosphorylated) which usually phosphorylates β-catenin at Ser33/37/Thr41. After MI, TGF-β1, and Wnt 1 levels are significantly increased, the overproduction of Wnt1 induces β-catenin stabilization and nuclear translocation through increasing the phosphorylation of disheveled (DVL) protein which in turn phosphorylates and inhibits GSK3β. TGF-β1 stimulates the phosphorylation of Smad-3 and subsequent nuclear translocation to activate the transcription of collage 1/III and α-smooth muscle actin (α-SMA). Besides, TGF-β1 stabilizes cytoplasmic β-catenin levels indirectly by phosphorylation of Akt at Thr308-induced inhibition of GSK3β by increasing phosphorylation of Ser9. Exendin-4, and possibly through G protein-coupled receptors (GPCRs), increases levels of cAMP and upregulates β-arrestin-2 levels. Both can result in a positive inotropic effect. Besides, β-arrestin-2 can stimulate PP2A to dephosphorylation Smad3 (inhibition) and GSK3β (activation), thus reduces fibrosis and prevents the activation of β-catenin and collagen deposition.
journal_name
Cardiovasc Drugs Therjournal_title
Cardiovascular drugs and therapyauthors
Eid RA,Khalil MA,Alkhateeb MA,Eleawa SM,Zaki MSA,El-Kott AF,Al-Shraim M,El-Sayed F,Eldeen MA,Bin-Meferij MM,Awaji KME,Shatoor ASdoi
10.1007/s10557-020-07006-9subject
Has Abstractpub_date
2020-05-30 00:00:00eissn
0920-3206issn
1573-7241pii
10.1007/s10557-020-07006-9pub_type
杂志文章abstract:OBJECTIVE:The natural history of pediatric patients with severely symptomatic neurocardiogenic syncope is poorly defined respect to the likelihood of remission or symptomatic recurrence along time. We undertook this study to investigate the likelihood of clinical relapse, and to assess the effect of prophylactic pharma...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1011179014084
更新日期:2001-03-01 00:00:00
abstract:BACKGROUND:Many studies have demonstrated a gap between guidelines for the prevention of cardiovascular disease (CVD) and their implementation in clinical practice. AIM:The PEGASE education program has been devised with an aim to improve the management of patients at high risk of CVD. METHODS:In a multicentre study c...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10557-008-6137-4
更新日期:2008-12-01 00:00:00
abstract:PURPOSE:Mechanical stretch is an arrhythmogenic factor found in situations of cardiac overload or dyssynchronic contraction. Ranolazine is an antianginal agent that inhibits the late Na (+) current and has been shown to exert a protective effect against arrhythmias. The present study aims to determine whether ranolazin...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-015-6587-4
更新日期:2015-06-01 00:00:00
abstract::The use of calcium antagonists and diuretics in combination for treatment of hypertension is controversial. In a single-blind study 16 patients (8 men, 8 women, age range 39 to 62 years) with primary hypertension of mild to moderate degree were given slow-release nifedipine 20 mg twice daily for 6 weeks, thereafter ei...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF02125751
更新日期:1988-03-01 00:00:00
abstract:PURPOSE:Although erythropoietin (EPO) is known to express angiogenic and cardioprotective effects, it also induces hypertension, polycythemia, and platelet activation, which may cause serious adverse effects in patients with cardiovascular diseases. We compared the angiogenic effects of EPO and its nonerythropoietic de...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-013-6438-0
更新日期:2013-04-01 00:00:00
abstract::To compare the antiischemic effects of intracoronary administration of a beta blocker, atenolol, and of a calcium antagonist, nifedipine, on the clinical and electrocardiographic signs of myocardial ischemia induced by balloon occlusion of the coronary artery, we studied 32 consecutive patients undergoing routine PTCA...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF00051147
更新日期:1992-06-01 00:00:00
abstract:BACKGROUND:Although Takotsubo syndrome (TS) was once considered to be rare and largely benign, it is now recognized to represent a major cause of cardiac morbidity and mortality, especially in ageing women. The biochemical precipitant of attacks of TS is an increase in catecholamine concentrations within the myocardium...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-019-06918-5
更新日期:2020-02-01 00:00:00
abstract::In the latter half of the 20th century, among participants of the Framingham Heart Study, incidence of heart failure (HF) has declined by about a third in women but not in men and survival after the onset of HF has improved in both sexes; however, HF remains highly lethal with over 50% dying within 5 years after onset...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/s10557-015-6599-0
更新日期:2015-08-01 00:00:00
abstract::The effects of administration of guava and papaya fruit (100 g/day), vegetables, and mustard oil (5 g/day) (group A); antioxidant vitamins C (50 mg/day) and E (30 mg/day), plus betacarotene (10 mg/day) (group B); a high-fat (5-10 g/day) (group C); or a low-fat (4-5 g/day) diet (group D) were compared over 24 diet week...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF00879869
更新日期:1995-12-01 00:00:00
abstract::Beneficial effects of monotherapy with ACE inhibitors or beta-blockers on hemodynamic function after myocardial infarction are well known. Until now, the effects of combined treatment on cardiac function and energy metabolism have been poorly described. This study examines the effects of combined ramipril and metoprol...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1007846311040
更新日期:2000-12-01 00:00:00
abstract::Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Par...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF00877749
更新日期:1995-02-01 00:00:00
abstract::The present study was undertaken on 10 patients with angina undergoing percutaneous transluminal coronary angioplasty. The angioplasty procedure consisted of two successive 30-second balloon inflations at 5 minute intervals. After the first inflation, nicorandil (0.1 mg/kg) was given intravenously over a 2-minute peri...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章
doi:10.1007/BF00878473
更新日期:1995-03-01 00:00:00
abstract::Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has be...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/s10557-018-6838-2
更新日期:2018-12-01 00:00:00
abstract::People who consume a diet rich in fruit and vegetables have lower risks of cancer, cardiovascular disease and all-cause mortality. Many prospective cohort studies have reported inverse associations between dietary intake or blood levels of beta-carotene and risks of cancer. Several large-scale trials were set up to as...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1023/a:1022134418372
更新日期:2002-09-01 00:00:00
abstract::Cardiovascular disease is the leading cause of death in men and women in the USA. Once a patient experiences an acute coronary syndrome (ACS), they are at increased risk for hospital readmission within 30 days and 6 months after discharge and more importantly, they have worse survival. Hospital readmissions lead to po...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-018-6798-6
更新日期:2018-12-01 00:00:00
abstract:AIMS:The primary ain of this study was to investigate the effect of carbachol on ventricular repolarisation in an intact animal heart. METHODS:In five sheep, carbachol was administered to the left circumflex coronary artery (LCX) at 1.0 and 2.5 micromol/ml/min respectively for 3 min. Multiple unipolar ECGs were acquir...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1027324412869
更新日期:2003-07-01 00:00:00
abstract::The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolariz...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1007830607733
更新日期:2000-06-01 00:00:00
abstract:PURPOSE:Dofetilide is class III antiarrhythmic agent which prolongs cardiac action potential duration because of selective inhibition of I (Kr), the rapid component of the delayed rectifier K(+) current. Although clinical studies reported on proarrhythmic risk associated with dofetilide treatment, the contributing elec...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-012-6405-1
更新日期:2012-12-01 00:00:00
abstract::Based on a retrospective analysis of the DAVIT II database, we attempted to propose subgroups of post-infarction patients with heart failure, who might benefit or not benefit from antiischemic medical intervention. In DAVIT II, patients were randomized in a double-blind fashion to either verapamil 360 mg/day or placeb...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1007/BF00877400
更新日期:1994-12-01 00:00:00
abstract::The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (4 mM) and at CL between 300 and 500...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF00054193
更新日期:1992-08-01 00:00:00
abstract:PURPOSE:To assess whether glycoprotein IIb/IIIa inhibition using tirofiban in low risk patients undergoing percutaneous coronary intervention (PCI) may reduce the risk of periprocedural myocardial infarction compared to standard care in poor responders to aspirin and/or clopidogrel. METHODS:We will enroll patients at ...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10557-008-6121-z
更新日期:2008-08-01 00:00:00
abstract::The pathogenetic theories and treatment of Raynaud's phenomenon are reviewed. In primary Raynaud's disease, most evidence supports a local defect at the digital artery level, with vasoconstriction or vasospasm of the digital arteries inducing the color changes. Normal sympathetic activity, low transmural arterial dist...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF00053426
更新日期:1990-01-01 00:00:00
abstract::In animal models, calcium antagonists (Ca-A) administered before ischemia and reperfusion reduced myocardial necrosis, attenuated postischemic contractile dysfunction, and reduced tissue calcium. In 753 patients with acute myocardial infarction (AMI), we examined if use of Ca-A at the onset of symptoms (n = 127 patien...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1007727518684
更新日期:1997-09-01 00:00:00
abstract::Vascular endothelium gene expression regulates blood-vessel wall interactions, vascular permeability, smooth muscle cell growth and tone. The possibility to introduce exogenous DNA or RNA sequences in endothelial cells represents a novel therapeutic approach of vascular disease. The aim of the work was to investigate ...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1011154616992
更新日期:2001-01-01 00:00:00
abstract::A succession of theories arising from last century has attempted to explain why patients with damaged hearts develop peripheral edema. Opposed to the original simple concepts of backward failure, a number of theories of forward failure have been proposed, the cardiac output being considered inadequate for capillary pe...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF00877921
更新日期:1994-06-01 00:00:00
abstract:INTRODUCTION:During and following cardiac ischemia the levels of circulating fatty acids are elevated, resulting in fatty acid oxidation dominating as a source of oxidative metabolism at the expense of pyruvate oxidation. A decrease in the levels of myocardial malonyl-CoA (an endogenous inhibitor of mitochondrial fatty...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/s10557-006-0634-0
更新日期:2006-12-01 00:00:00
abstract:OBJECTIVE:Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Ai...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-008-6117-8
更新日期:2008-10-01 00:00:00
abstract::In patients with hypertension persisting on combined diuretic and beta-blocker therapy, the effects of an additional 9-week therapy with a calcium antagonist (nifedipine) versus a classical arterial vasodilator (hydralazine) were compared for changes in blood pressure (BP), plasma catecholamines (n = 15), and left ven...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF01857760
更新日期:1990-04-01 00:00:00
abstract::Milrinone is shown in 10 patients to be a valuable pharmacological bridge to heart transplantation; it can stabilize and improve decompensated chronic heart failure (CHF) in cases where the response to beta-agonists is inadequate. One patient who had suffered an acute myocardial infarction with heart failure resistant...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF00877820
更新日期:1993-08-01 00:00:00
abstract::The place of digoxin in the pediatric cardiologist's armamentarium remains uncertain. As an antiarrhythmic, its use in the Wolff-Parkinson-White syndrome is obsolete, but it remains useful in the treatment of the chronic atrial fibrillation seen in some patients postoperatively and in children with dilated cardiomyopa...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF01881525
更新日期:1989-03-01 00:00:00