scholarly journals Cardioprotective Effect of Novel Matrix Metalloproteinase Inhibitors

2020 ◽  
Vol 21 (19) ◽  
pp. 6990
Author(s):  
Kamilla Gömöri ◽  
Tamara Szabados ◽  
Éva Kenyeres ◽  
Judit Pipis ◽  
Imre Földesi ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Positive Control ◽  
Matrix Metalloproteinase 2 ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride

Background: We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. Methods: Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. Results: MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. Conclusions: This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

scholarly journals Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia–reperfusion Injury in Rodents

2016 ◽  
Vol 125 (6) ◽  
pp. 1171-1180 ◽  
Author(s):  
Yao Lu ◽  
Honit Piplani ◽  
Stacy L. McAllister ◽  
Carl M. Hurt ◽  
Eric R. Gross
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
In Vivo Model

Abstract Background Recent evidence suggests that cross talk exists between cellular pathways important for pain signaling and ischemia–reperfusion injury. Here, the authors address whether the transient receptor potential ankyrin 1 (TRPA1) channel, important in pain signaling, is present in cardiac myocytes and regulates cardiac ischemia–reperfusion injury. Methods For biochemical analysis of TRPA1, techniques including quantitative polymerase chain reaction, Western blot, and immunofluorescence were used. To determine how TRPA1 mediates cellular injury, the authors used an in vivo model of rat cardiac ischemia–reperfusion injury and adult rat–isolated cardiac myocytes subjected to hypoxia–reoxygenation. Results The authors’ biochemical analysis indicates that TRPA1 is within the cardiac myocytes. Further, using a rat in vivo model of cardiac injury, the TRPA1 activators ASP 7663 and optovin reduce myocardial injury (45 ± 5%* and 44 ± 8%,* respectively, vs. control, 66 ± 6% infarct size/area at risk; n = 6 per group; mean ± SD; *P < 0.001). TRPA1 inhibition also blocked the infarct size–sparing effects of morphine. In isolated cardiac myocytes, the TRPA1 activators ASP 7663 and optovin reduce cardiac myocyte cell death when given during reoxygenation (20 ± 3%* and 22 ± 4%* vs. 36 ± 3%; percentage of dead cells per field, n = 6 per group; mean ± SD; *P < 0.05). For a rat in vivo model of cardiac injury, the infarct size–sparing effect of TRPA1 activators also occurs during reperfusion. Conclusions The authors’ data suggest that TRPA1 is present within the cardiac myocytes and is important in regulating myocardial reperfusion injury. The presence of TRPA1 within the cardiac myocytes may potentially explain why certain pain relievers that can block TRPA1 activation, such as cyclooxygenase-2 inhibitors or some nonsteroidal antiinflammatory drugs, could be associated with cardiovascular risk.

Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation

2007 ◽  
Vol 292 (6) ◽  
pp. H3158-H3163 ◽  
Author(s):  
Aliaksandr Bulhak ◽  
Joy Roy ◽  
Ulf Hedin ◽  
Per-Ove Sjöquist ◽  
John Pernow
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Control Group ◽  
Geranylgeranyl Pyrophosphate ◽  
Rhoa Protein ◽  
Coa Reductase

Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion whereat infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 ± 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 ± 2% ( P < 0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 ± 2%, P < 0.01 vs. rosuvastatin) but not methanol (65 ± 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 ± 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium ( P < 0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.

scholarly journals Comparative Effects of Verapamil, Nicardipine, and Nitroglycerin on Myocardial Ischemia/Reperfusion Injury

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Hitoshi Yui ◽  
Uno Imaizumi ◽  
Hisashi Beppu ◽  
Mitsuhiro Ito ◽  
Munetaka Furuya ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rabbit Model ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Control Group ◽  
Area At Risk ◽  
Group A

The aim of this experiment was to establish whether verapamil, nicardipine, and nitroglycerin have (1) infarct size-limiting effects and (2) antiarrhythmic effects inin vivorabbit hearts during ischemia/reperfusion. Rabbits received regional ischemia by 30 min of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion under ketamine and xylazine anesthesia. The animals were randomly assigned to the following 4 treatment groups: a control group, a verapamil group, a nicardipine group, and a nitroglycerin group. A continuous infusion of verapamil, nicardipine, or nitroglycerin was initiated 5 min prior to ischemia. Infarct size/area at risk decreased in verapamil, and nitroglycerin. The incidence of ischemia-induced arrhythmia decreased in nicardipine, verapamil and nitroglycerin. The incidence of reperfusion-induced arrhythmias decreased in verapamil and nitroglycerin. From the present experimental results, verapamil and nitroglycerin rather than nicardipine did afford significant protection to the heart subjected to ischemia and reperfusion in a rabbit model.

Effects of Endotoxin on Neutrophil-Mediated Ischemia/Reperfusion Injury in the Rat Heart In Vivo

2001 ◽  
Vol 226 (4) ◽  
pp. 320-327 ◽  
Author(s):  
Brian P. Lipton ◽  
Joseph B. Delcarpio ◽  
Kathleen H. McDonough
Keyword(s):  
At Risk ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Necrotic Area ◽  
Area At Risk

We have previously shown that a nonlethal dose of lipopolysaccharide (LPS) decreases L-selectin expression of neutrophils (PMNs), thereby preventing PMN-mediated reperfusion injury in the isolated heart. In the present study we determined whether or not that dose of LPS would protect hearts during in vivo ischemia and reperfusion by preventing PMN-induced reperfusion injury. Rats receiving saline vehicle showed marked myocardial injury (necrotic area/area at risk = 82% ± 2%) and significant depression in left ventricular function as assessed in the isolated isovolumic heart preparation at constant flow rates of 5, 10, 15, and 20 ml/min. The administration of LPS (100 μg/kg body wt) 7 hr prior to ischemia resulted in a reduction in myocardial damage (necrotic area/area at risk = 42% ± 3%) and preservation of function. Myocardial function was similar to that of sham ischemic saline- and LPS-treated rats. Moreover, PMN infiltration as determined by histology was quantitatively more severe in hearts of saline-treated rats than in hearts of LPS-treated rats. Isolated hearts from vehicle- and LPS-treated animals undergoing sham ischemia in vivo recovered to the same extent after in vitro ischemia/reperfusion, suggesting that LPS did not induce protection by altering intrinsic properties of the heart. Our results indicate that LPS-induced protection of the heart from in vivo PMN-mediated ischemia/reperfusion injury may be due to decreased L-selectin expression of PMNs in LPS-treated animals.

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.

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.

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