Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury

2005 ◽  
Vol 289 (5) ◽  
pp. H2265-H2271 ◽  
Author(s):  
Jiangning Tan ◽  
Zhizhong Ma ◽  
Ling Han ◽  
Ruyu Du ◽  
Liming Zhao ◽  
...  
Keyword(s):  
At Risk ◽  
Cell Death ◽  
Myocardial Ischemia ◽  
Caffeic Acid ◽  
Ischemia Reperfusion ◽  
Caffeic Acid Phenethyl Ester ◽  
Acute Myocardial Ischemia ◽  
Area At Risk ◽  
Cardioprotective Effects ◽  
Myocardial Ischemia Reperfusion

Although great achievements have been made in elucidating the molecular mechanisms contributing to acute myocardial ischemia/reperfusion (I/R) injury, an effective pharmacological therapy to protect cardiac tissues from serious damage associated with acute myocardial infarction, coronary arterial bypass grafting surgery, or acute coronary syndromes has not been developed. We examined the in vivo cardioprotective effects of caffeic acid phenethyl ester (CAPE), a natural product with potent anti-inflammatory, antitumor, and antioxidant activities. CAPE was systemically delivered to rabbits either 60 min before or 30 min after surgically inducing I/R injury. Infarct dimensions in the area at risk were reduced by >2-fold ( P < 0.01) with CAPE treatment at either period. Accordingly, serum levels of normally cytosolic enzymes lactate dehydrogenase, creatine kinase (CK), MB isoenzyme of CK, and cardiac-specific troponin I were markedly reduced in both CAPE treatment groups ( P < 0.05) compared with the vehicle-treated control group. CAPE-treated tissues displayed significantly less cell death ( P < 0.05), which was in part due to inhibition of p38 mitogen-activated protein kinase activation and reduced DNA fragmentation often associated with caspase 3 activation ( P < 0.05). In addition, CAPE directly blocked calcium-induced cytochrome c release from mitochondria. Finally, the levels of inflammatory proteins IL-1β and TNF-α expressed in the area at risk were significantly reduced with CAPE treatment ( P < 0.05). These data demonstrate that CAPE has potent cardioprotective effects against I/R injury, which are mediated, at least in part, by the inhibition of inflammatory and cell death responses. Importantly, protection is conferred when CAPE is systemically administered after the onset of ischemia, thus demonstrating potential efficacy in the clinical scenario.

Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion

1992 ◽  
Vol 263 (3) ◽  
pp. H771-H777 ◽  
Author(s):  
M. R. Siegfried ◽  
C. Carey ◽  
X. L. Ma ◽  
A. M. Lefer
Keyword(s):  
At Risk ◽  
Endothelial Dysfunction ◽  
Myocardial Ischemia ◽  
Ethyl Ester ◽  
Ischemia Reperfusion ◽  
Myocardial Oxygen Demand ◽  
Area At Risk ◽  
No Donor ◽  
Beneficial Effects ◽  
Myocardial Ischemia Reperfusion

Intravenous administration of SPM-5185 [N-nitratopivaloyl-S-(N–-acetylalanyl)-cysteine ethyl ester], a cysteine-containing nitric oxide (NO) donor, or SPM-5267 [pivaloyl-S-(N–-acetylalanyl)-cysteine ethyl ester], an analogue of SPM-5185 that lacks the NO moiety, was studied in a feline myocardial ischemia-reperfusion model. Administration of SPM-5185 (1 mg/kg), followed by a 2-mg.kg-1.h-1 infusion starting 10 min before reperfusion, resulted in significant protection 4.5 h postreperfusion. In the myocardial ischemia (MI)+SPM-5267 group, 38 +/- 4% of the area at risk was necrotic, whereas the necrotic area/area at risk was only 7 +/- 2% in the MI+SPM-5185 group (P less than 0.01). Moreover, SPM-5185 treatment markedly attenuated the endothelial dysfunction observed in the left anterior descending coronary artery after reperfusion by 50%. These beneficial effects occurred despite the absence of a significant change in myocardial oxygen demand, as measured by the pressure-rate index. In vitro experiments demonstrated that SMP-5185, but not SPM-5267, decreased adherence of neutrophils to the coronary vascular endothelium and decreased production of superoxide radicals. Therefore, a likely mechanism of the observed cardioprotection by SPM-5185 involves attenuation of polymorphonuclear leukocyte-induced endothelial dysfunction.

MYOCARDIAL ISCHEMIA/REPERFUSION-INDUCED OXIDATIVE RENAL DAMAGE IN RATS: PROTECTION BY CAFFEIC ACID PHENETHYL ESTER (CAPE)

Shock ◽  
2005 ◽  
Vol 24 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Mehmet Kaya Ozer ◽  
Hakan Parlakpinar ◽  
Nigar Vardi ◽  
Yilmaz Cigremis ◽  
Muharrem Ucar ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Caffeic Acid ◽  
Renal Damage ◽  
Ischemia Reperfusion ◽  
Caffeic Acid Phenethyl Ester ◽  
Myocardial Ischemia Reperfusion

Abstract 714: Targeting Coagulation Factor XII to Protect from Cardiac Ischemia Reperfusion Injury

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Stefan Frantz ◽  
Johann Bauersachs ◽  
Anna Adamek ◽  
Nadja Blomer ◽  
Georg Ertl ◽  
...  
Keyword(s):  
At Risk ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Factor Xii ◽  
Area At Risk ◽  
Infarct Area ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis and thus exaggerate myocardial ischemia/reperfusion injury. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, but can reduce thrombus formation. Therefore, we studied the contribution of FXII for myocardial ischemia reperfusion injury. Following 30 minutes of ischemia and 24 hours of reperfusion infarct size in FXII deficient mice was significantly reduced as compared to wild type controls (infarct/area at risk, WT vs. FXII−/−, 73.5%±4.4% vs. 42.3±1.6%, p<0.001) despite similar area at risk (WT vs. FXII−/−, 28.3%±1.7% vs. 29.9±1.0%, p=n.s.). There was no difference in bleeding complications and bleeding time. Mice deficient in the FXII substrate factor XI were similarly protected from ischemia reperfusion injury (infarct/area at risk, FXI−/−, 16.9%±4.1%, vs. WT p<0.001). The phenotype of FXII−/−mice could be rescued by intravenous application of human FXII (infarct/area at risk, FXII−/−+FXII, 77.3%±8.4%, p<0.001 vs. FXIIKO). WT mice treated with the FXII inhibitor PCK (Pro-Phe-Arg-chloromethylketone) were similarly protected from myocardial ischemia/reperfusion injury (infarct/area at risk, 46.5% ±3.7%, vs. WT p<0.001). The data suggest that the intrinsic pathway is crucial for pathological clotting in myocardial ischemia reperfusion injury. FXII inhibition may offer a selective and safe strategy to reduce ischemic injury.

Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury

2006 ◽  
Vol 291 (1) ◽  
pp. H379-H384 ◽  
Author(s):  
Ryuji Hataishi ◽  
Ana Clara Rodrigues ◽  
Tomas G. Neilan ◽  
John G. Morgan ◽  
Emmanuel Buys ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
At Risk ◽  
Myocardial Ischemia ◽  
Murine Model ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Lv Function ◽  
Area At Risk ◽  
Myocardial Ischemia Reperfusion ◽  
Hemodynamic Measurements

To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury.

Abstract 350: Toll-like Receptor 2 Activation, Especially In Circulating Leukocytes, Mediates Myocardial Ischemia/Reperfusion Injury In Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Fatih Arslan ◽  
Gerard Pasterkamp ◽  
Leo Timmers ◽  
Ben van Middelaar ◽  
Pieter A Doevendans ◽  
...  
Keyword(s):  
At Risk ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Blue Dye ◽  
Tlr2 Expression ◽  
Area At Risk ◽  
Saline Treatment ◽  
Myocardial Ischemia Reperfusion

OBJECTIVES. Myocardial ischemia/reperfusion (MI/R) injury is characterized by an inflammatory response through NF-κB, increase of infarct size and worsening of cardiac function. Toll-like receptors (TLRs) are part of innate immunity and initiate the same inflammatory reaction. Here we studied in vivo to what extent TLR2 is involved in myocardial damage and what the relative contribution is of TLR2 expression in parenchymal cells and leukocytes to myocardial damage during MI/R in mice. METHODS. C57Bl6J mice underwent 30 minutes ischemia - 24 hours of reperfusion. Four experimental groups were studied: TLR2 knock-out (TLR2 KO) mice (n=10), saline treated wild-type (WT) mice (n=10), generated chimeric WT mice with TLR2 KO bone marrow (BLOOD KO; n=7) and chimeric TLR2 KO mice with WT hematopoietic cells (ORGAN KO; n=7). Saline was administered via the tail vein 5 minutes prior to reperfusion. After 24 hours, the LCA was ligated again at the level marked by the suture left in place. Mice were terminated and infarct size (IS) was measured as a percentage of the area at risk (AAR) using 4% Evans’ blue dye injection in the aortic root and triphenyltetrazolium chloride (TTC) staining (fig. 1). Data are presented as Mean±SEM. RESULTS. The AAR as percentage of the left ventricle was similar between groups: TLR2 KO 41%, saline 41%, Blood KO 41%, Organ KO 42%. Saline treatment resulted in 34.5%±3.3 of infarction, whereas in TLR2 KO mice infarct size decreased to 23.0%±2.9 (p=0.029 vs. saline). Infarct size in BLOOD KO mice was 22.9%±2.7 (p=0.024 vs. saline), while ORGAN KO mice had 33.9%±3.2 (p=0.998 vs. saline) of infarction within the area at risk (fig. 2). CONCLUSION. TLR2 deficiency significantly reduces infarct size with ~33% compared to saline treatment in mice after 30 minutes of ischemia and 24 hours of reperfusion. We show for the first time that TLR2 expression in circulating leukocytes plays an important role in infarction after MI/R injury. Systemic inhibition of TLR2 may be a potential therapeutic target in the treatment of patients with acute myocardial infarction.

Abstract 446: Activation of γ2-ampk Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia-reperfusion Injury

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yang Cao ◽  
Naveen Bojjireddy ◽  
Maengjo Kim ◽  
Tao Li ◽  
Peiyong Zhai ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Area At Risk ◽  
Stress Markers ◽  
Myocardial Ischemia Reperfusion

AMP-activated protein kinase (AMPK) is a heterotrimeric protein that senses cellular energy status and maintains energy homeostasis by switching off biosynthetic pathways and increasing catabolism. The subcellular localization of AMPK has been shown to affect its activation and function. The γ2 subunit has both nuclear localization sequence and nuclear export sequence suggesting that it can shuttle between the two compartments. By overexpressing GFP-tagged γ subunits in COS7 cells followed by glucose deprivation or AMPK activation (A769662), we demonstrated that AMPK containing γ2 but not γ1 or γ3 subunit translocates into nucleus. Nuclear accumulation of AMPK complexes containing γ2-subunit phosphorylates and inactivates Pol I-associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes and lowering preribosomal RNA (pre-rRNA) level. Down-regulation of rRNA synthesis attenuated expression of ER stress markers (spliced X-box binding protein-1 and C/EBP homologous protein) and ER stress-induced cell death. Deleting γ2-AMPK using CRISPR-Cas9 system led to increases in pre-rRNA level, ER stress markers and cell death during glucose deprivation. To study the function of γ2-AMPK in the heart, we generated a mouse model with cardiac specific deletion of γ2-AMPK (cKO). Although the total AMPK activity was unaltered in cKO hearts due to upregulation of γ1-AMPK the lack of γ2-AMPK sensitizes the heart to myocardial ischemia-reperfusion (I/R, 30min ischemia followed by 24hr reperfusion) injury as evidenced by larger infarct size (Infarct size/area at risk: 34.7±5.7% vs. 50.6±8.9%, for control and cKO respectively, P<0.05). The cKO failed to suppress pre-rRNA level during I/R and showed higher levels of ER stress markers. Conversely, cardiac-specific overexpression (OE) of γ2-AMPK decreased ER stress markers and pre-rRNA level upon I/R injury and the infarct size was reduced (Infarct size/area at risk: 26.8±6.5% for control vs. 15.8±3.7% for OE, P<0.05), suggesting that γ2-AMPK protects against I/R injury and ER stress in the heart. Taken together, our study reveals isoform-specific functions of γ2-AMPK in modulating protein synthesis, cell survival and cardioprotection.

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