Adrenomedullin gene delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion

2003 ◽  
Vol 285 (4) ◽  
pp. H1506-H1514 ◽  
Author(s):  
Kazuo Kato ◽  
Hang Yin ◽  
Jun Agata ◽  
Hideaki Yoshida ◽  
Lee Chao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Infarct Size ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Area At Risk ◽  
Calcitonin Gene ◽  
Myocardial Ischemia Reperfusion

Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia-reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide [CGRP(8–37)]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the Akt-Bad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.

scholarly journals Metoprolol blunts the time-dependent progression of infarct size

2020 ◽  
Vol 115 (5) ◽  
Author(s):  
Manuel Lobo-Gonzalez ◽  
Carlos Galán-Arriola ◽  
Xavier Rossello ◽  
Maribel González‐Del‐Hoyo ◽  
Jean Paul Vilchez ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Primary Angioplasty ◽  
Primary Outcome Measure ◽  
Artery Occlusion ◽  
Area At Risk ◽  
Perfusion Computed Tomography ◽  
Myocardial Ischemia Reperfusion

Abstract Early metoprolol administration protects against myocardial ischemia–reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.

Long-term infusion of Met5-enkephalin fails to protect murine hearts against ischemia-reperfusion injury

2005 ◽  
Vol 288 (4) ◽  
pp. H1717-H1723 ◽  
Author(s):  
Koh Kuzume ◽  
Kazuyo Kuzume ◽  
Zhiping Cao ◽  
Lijuan Liu ◽  
Donna M. Van Winkle
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Opioid Peptide ◽  
Area At Risk ◽  
Regional Myocardial Ischemia ◽  
Chronic Infusion ◽  
Myocardial Ischemia Reperfusion

Recently, we reported that exogenous administration of Met5-enkephalin (ME) for 24 h reduces infarct size after ischemia-reperfusion in rabbits. In the present study, we tested whether ME-induced cardioprotection is exhibited in murine hearts and whether chronic infusion of this peptide can render hearts tolerant to ischemia. Barbiturate-anesthetized open-chest mice (C57BL/6J) were subjected to regional myocardial ischemia-reperfusion (45 min of occlusion and 20 min of reperfusion). Mice received saline vehicle or ME for 24 h or 2 wk before undergoing regional myocardial ischemia-reperfusion or for 24 h followed by a 24-h delay before regional myocardial ischemia-reperfusion. Infarct size was measured with propidium iodide and is expressed as a percentage of the area at risk. Infarcts were smaller after infusion of ME for 24 h than with vehicle control: 49.2 ± 9.0% vs. 22.2 ± 3.2% ( P < 0.01). In contrast, administration of ME for 2 wk failed to elicit cardioprotection: 36.5 ± 9.1% and 41.4 ± 8.2% for control and ME, respectively ( P = not significant). When a 24-h delay was imposed between the end of drug treatment and the onset of the ischemic insult, cardioprotection was lost: 38.5 ± 6.1% and 42.8 ± 6.6% for control and ME, respectively ( P = not significant). Chronic sustained exogenous infusion of the endogenously produced opioid peptide ME is associated with loss of the cardioprotection that is observed with 24 h of infusion. Furthermore, in this in vivo murine model, ME failed to induce delayed tolerance to myocardial ischemia-reperfusion.

Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury

1998 ◽  
Vol 275 (5) ◽  
pp. H1865-H1872 ◽  
Author(s):  
Anthony J. Palazzo ◽  
Steven P. Jones ◽  
Donald C. Anderson ◽  
D. Neil Granger ◽  
David J. Lefer
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia Reperfusion

We investigated in vivo coronary P-selectin expression and its pathophysiological consequences in a murine model of myocardial ischemia-reperfusion (MI/R) using wild-type and P-selectin deficient (−/−) mice. Coronary P-selectin expression [μg monoclonal antibody (MAb)/g tissue] was measured using a radiolabeled MAb method after 30 min of myocardial ischemia and 20 min of reperfusion. P-selectin expression in wild-type mice was significantly ( P< 0.01) elevated in the ischemic zone (0.070 ± 0.010) compared with the nonischemic zone (0.037 ± 0.008). Myocardial P-selectin expression was nearly undetectable in P-selectin −/− mice after MI/R. Furthermore, myocardial infarct size (% of area at risk) after 30 min of myocardial ischemia and 120 min of reperfusion was 42.5 ± 4.4 in wild-type mice and 24.4 ± 4.0 in P-selectin −/− mice ( P < 0.05). In additional experiments of prolonged myocardial ischemia (60 min) and reperfusion (120 min), myocardial infarct size was similar in P-selectin −/− mice and wild-type mice. Our results clearly demonstrate the involvement of coronary P-selectin in the development of myocardial infarction after MI/R.

scholarly journals Effects on cardiac function, remodeling and inflammation following myocardial ischemia–reperfusion injury or unreperfused myocardial infarction in hypercholesterolemic APOE*3-Leiden mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Niek J. Pluijmert ◽  
Cindy I. Bart ◽  
Wilhelmina H. Bax ◽  
Paul H. A. Quax ◽  
Douwe E. Atsma
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trials ◽  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Apo E ◽  
Lv Remodeling ◽  
Myocardial Ischemia Reperfusion

Abstract Many novel therapies to treat myocardial infarction (MI), yielding promising results in animal models, nowadays failed in clinical trials for several reasons. The most used animal MI model is based on permanent ligation of the left anterior descending (LAD) coronary artery in healthy mice resulting in transmural MI, while in clinical practice reperfusion is usually accomplished by primary percutaneous coronary interventions (PCI) limiting myocardial damage and inducing myocardial ischemia–reperfusion (MI-R) injury. To evaluate a more similar murine MI model we compared MI-R injury to unreperfused MI in hypercholesterolemic apolipoprotein (APO)E*3-Leiden mice regarding effects on cardiac function, left ventricular (LV) remodeling and inflammation. Both MI-R and MI resulted in significant LV dilation and impaired cardiac function after 3 weeks. Although LV dilation, displayed by end-diastolic (EDV) and end-systolic volumes (ESV), and infarct size (IS) were restricted following MI-R compared to MI (respectively by 27.6% for EDV, 39.5% ESV, 36.0% IS), cardiac function was not preserved. LV-wall thinning was limited with non-transmural LV fibrosis in the MI-R group (66.7%). Two days after inducing myocardial ischemia, local leucocyte infiltration in the infarct area was decreased following MI-R compared to MI (36.6%), whereas systemic circulating monocytes were increased in both groups compared to sham (130.0% following MI-R and 120.0% after MI). Both MI-R and MI models against the background of a hypercholesterolemic phenotype appear validated experimental models, however reduced infarct size, restricted LV remodeling as well as a different distributed inflammatory response following MI-R resemble the contemporary clinical outcome regarding primary PCI more accurately which potentially provides better predictive value of experimental therapies in successive clinical trials.

Abstract 843: Cardiomyocyte Overexpression of the Hydrogen Sulfide Producing Enzyme Cystathioine gamma-Lyase Attenuates Myocardial Ischemia-Reperfusion Injury

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John W Elrod ◽  
John W Calvert ◽  
Chi-Wing Chow ◽  
Joanna Morrison ◽  
Jeannette E Doeller ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Area At Risk ◽  
Physiological Processes ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Background : Hydrogen sulfide (H 2 S) was recently discovered to be an endogenously produced gaseous second messenger capable of modulating many physiological processes. We have previously demonstrated that administration of a H 2 S donor limits the extent of myocardial infarction. This prompted us to investigate the potential of endogenously generated H 2 S in acute cardioprotection utilizing mice with transgenic overexpression of an H 2 S producing enzyme. Methods: Mice with cardiac-specific overexpression of murine cystathionine γ-lyase (αMHC-CGL-Tg) were generated and analyzed for increased enzyme expression and H 2 S production utilizing a H 2 S specific polarographic electrode. αMHC-CGL-Tg and WT mice were then subjected to 45 min of in vivo LCA ischemia and 72 hr reperfusion and infarct size was evaluated using TTC staining. Results: αMHC-CGL-Tg mice displayed an increased level of myocardial CGL RNA, which translated into a (15 fold) increase in protein expression. This increase in CGL enzyme resulted in a significant (2 fold) increase in H 2 S production by myocardial homogenates of αMHC-CGL-Tg mice. αMHC-CGL-Tg mice were found to have a 47% reduction in infarct size per area-at-risk (INF/AAR) as compared to WT littermates. AAR was similar between both groups. Conclusions: This is the first evidence that overexpression of a H 2 S producing enzyme can decrease infarct size following MI-R injury. These findings demonstrate that modulation of endogenous H 2 S production may be of clinical benefit in ischemic disorders and that H 2 S generating enzymes may be viable therapeutic targets.

A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo

2007 ◽  
Vol 292 (4) ◽  
pp. H1828-H1835 ◽  
Author(s):  
Giuseppina Milano ◽  
Sandrine Morel ◽  
Christophe Bonny ◽  
Michele Samaja ◽  
Ludwig K. von Segesser ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Peptide Inhibitor ◽  
Myocardial Ischemia Reperfusion

The c-Jun NH2-terminal kinase (JNK) pathway of the mitogen-activated protein kinase (MAPK) signaling cascade regulates cell function and survival after stress stimulation. Equally robust studies reported dichotomous results suggesting both protective and detrimental effects of JNK during myocardial ischemia-reperfusion (I/R). The lack of a highly specific JNK inhibitor contributed to this controversy. We recently developed a cell-penetrating, protease-resistant peptide inhibitor of JNK, d-JNKI-1. Here we report on the effects of d-JNKI-1 in myocardial I/R. d-JNKI-1 was tested in isolated-perfused adult rat hearts. Increased activation of JNK, p38-MAPK, and extracellular signal-regulated kinase-1/2 (ERK1/2), as assessed by kinase assays and Western blotting, occurred during I/R. d-JNKI-1 delivered before onset of ischemia prevented the increase in JNK activity while not affecting ERK1/2 and p38-MAPK activation. JNK inhibition reduced ischemic injury, as manifested by increased time to contracture ( P < 0.05) and decreased left ventricular end-diastolic pressure during ischemia ( P < 0.01), and enhanced posthypoxic recovery of systolic and diastolic function ( P < 0.01). d-JNKI-1 reduced mitochondrial cytochrome- c release, caspase-3 activation, and the number of apoptotic cells determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling ( P < 0.05), indicating suppression of the mitochondrial machinery of apoptosis. d-JNKI-1 delivered at the time of reperfusion did not improve functional recovery but still prevented apoptosis. In vivo, d-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by ∼50% ( P < 0.01). In conclusion, d-JNKI-1 is an important compound that can be used in preclinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.

scholarly journals Human Lysyl Oxidase Over-Expression Enhances Baseline Cardiac Oxidative Stress but Does Not Aggravate ROS Generation or Infarct Size Following Myocardial Ischemia-Reperfusion

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 75
Author(s):  
Laura Valls-Lacalle ◽  
Lídia Puertas-Umbert ◽  
Saray Varona ◽  
José Martínez-González ◽  
Cristina Rodríguez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Infarct Size ◽  
Cardiac Remodeling ◽  
Lysyl Oxidase ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Over Expression ◽  
Myocardial Oxidative Stress ◽  
Myocardial Ischemia Reperfusion

Lysyl oxidase (LOX) is an enzyme critically involved in collagen maturation, whose activity releases H2O2 as a by-product. Previous studies demonstrated that LOX over-expression enhances reactive oxygen species (ROS) production and exacerbates cardiac remodeling induced by pressure overload. However, whether LOX influences acute myocardial infarction and post-infarct left ventricular remodeling and the contribution of LOX to myocardial oxidative stress following ischemia-reperfusion have not been analyzed. Isolated hearts from transgenic mice over-expressing human LOX in the heart (TgLOX) and wild-type (WT) littermates were subjected to global ischemia and reperfusion. Although under basal conditions LOX transgenesis is associated with higher cardiac superoxide levels than WT mice, no differences in ROS production were detected in ischemic hearts and a comparable acute ischemia-reperfusion injury was observed (infarct size: 56.24 ± 9.44 vs. 48.63 ± 2.99% of cardiac weight in WT and TgLOX, respectively). Further, similar changes in cardiac dimensions and function were observed in TgLOX and WT mice 28 days after myocardial infarction induced by transient left anterior descending (LAD) coronary artery occlusion, and no differences in scar area were detected (20.29 ± 3.10 vs. 21.83 ± 2.83% of left ventricle). Our data evidence that, although LOX transgenesis induces baseline myocardial oxidative stress, neither ROS production, infarct size, nor post-infarction cardiac remodeling were exacerbated following myocardial ischemia-reperfusion.

scholarly journals ADAMTS13 Deficiency Exacerbates VWF-Dependent Acute Myocardial Ischemia/Reperfusion Injury in Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 264-264 ◽  
Author(s):  
Chintan Gandhi ◽  
David G Motto ◽  
Melissa Jensen ◽  
Steven R. Lentz ◽  
Anil K Chauhan
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Adamts13 Deficiency ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocyte Apoptosis ◽  
Myocardial Ischemia Reperfusion

Abstract Abstract 264 Background and objective: ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in thrombus formation by binding to platelets following vascular injury. Epidemiological studies suggest that elevated VWF levels and reduced ADAMTS13 activity in the plasma are risk factors for myocardial infarction. It remains unknown, however, whether the ADAMTS13-VWF axis plays a causal role in the pathophysiology of myocardial infarction. We tested the hypothesis that ADAMTS13 reduces VWF-mediated acute myocardial ischemia/reperfusion (I/R) injury in mice. Methods: Myocardial infarction was induced in male mice (8–10 weeks of age) by ligating the left anterior descending coronary artery for 30 minutes followed by 23.5 hours of reperfusion. The extent of myocardium damage was evaluated by measuring infarct size (%) in 2 mm serial sections stained with 2% triphenyl-2, 3, 4-tetrazolium-chloride. Neutrophil infiltration and myocyte apoptosis in the left ventricular area was quantified by immunohistochemistry and TUNEL staining respectively. Results: Adamts13 -/- mice exhibited significantly increased infarct size (22.2 % ± 1.1 %, P <.01) compared with WT mice (16.9 % ± 1.2 %, P<0.05). Plasma levels of cardiac troponin T (cTnT), an index of myocyte injury, were significantly higher in Adamts13−/− mice compared with WT mice (P <0.01). Adamts13+/− mice, which have a 50% reduction in ADAMTS13 activity, had similar sized infarcts (16.6 ± 1.3%) and cTnT levels compared to those in WT mice. Larger infarcts in the Adamts13−/− mice were concordant with increased neutrophil infiltration and myocyte apoptosis compared with WT mice. Because VWF remains the only known substrate of ADAMTS13 in multiple experimental models, we hypothesized that ADAMTS13 reduces myocardial injury through its proteolytic effect on hyper adhesive ULVWF and /or VWF. Vwf−/− mice exhibited significantly reduced infarct size, neutrophil infiltration, and myocyte apoptosis compared with WT mice, suggesting a detrimental role for VWF in myocardial I/R injury. VWF-deficient mice have a defect in regulation of endothelial P-selectin due to the loss of Weibel-Palade body formation. To confirm that exacerbated myocardial I/R injury in the setting of ADAMTS13 deficiency is dependent on VWF rather than P-selectin, we compared WT and Adamts13−/− mice treated with anti-VWF inhibitory antibodies. Treating WT or Adamts13−/− mice with neutralizing antibodies to VWF prior to myocardial I/R injury significantly reduced infarct size compared with control Ig-treated mice, suggesting that exacerbated myocardial I/R injury observed in Adamts13−/− mice is entirely VWF-dependent. Finally, myocardial I/R injury in Adamts13−/−/Vwf−/− mice was similar to that in Vwf−/− mice, suggesting that the exacerbated myocardial I/R injury observed in the setting of ADAMTS13 deficiency is VWF-dependent. Conclusion: These findings reveal a new role for anti-thrombotic enzyme ADAMTS13 in reducing VWF-mediated myocardial ischemia/reperfusion injury. Disclosures: Lentz: Novo Nordisk A/S: Consultancy, Investigator Other.

scholarly journals Exercise and Cardioprotection: A Natural Defense Against Lethal Myocardial Ischemia–Reperfusion Injury and Potential Guide to Cardiovascular Prophylaxis

2018 ◽  
Vol 24 (1) ◽  
pp. 18-30 ◽  
Author(s):  
Mohammed Andaleeb Chowdhury ◽  
Haden K. Sholl ◽  
Megan S. Sharrett ◽  
Steven T. Haller ◽  
Christopher C. Cooper ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Beneficial Effects ◽  
Natural Defense ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Similar to ischemic preconditioning, high-intensity exercise has been shown to decrease infarct size following myocardial infarction. In this article, we review the literature on beneficial effects of exercise, exercise requirements for cardioprotection, common methods utilized in laboratories to study this phenomenon, and discuss possible mechanisms for exercise-mediated cardioprotection.

Sign in / Sign up

Export Citation Format

Share Document