scholarly journals Modification of Cardiac Progenitor Cell-Derived Exosomes by miR-322 Provides Protection against Myocardial Infarction through Nox2-Dependent Angiogenesis

Antioxidants ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 18 ◽  
Author(s):  
Seock-Won Youn ◽  
Yang Li ◽  
Young-Mee Kim ◽  
Varadarajan Sudhahar ◽  
Kareem Abdelsaid ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion Injury ◽  
Capillary Tube ◽  
Ischemia Reperfusion ◽  
Direct Injection ◽  
Cardiac Injury ◽  
Tube Formation ◽  
Acute Ischemia ◽  
Paracrine Effects ◽  
Border Zones

Myocardial infarction (MI) is the primary cause of cardiovascular mortality, and therapeutic strategies to prevent or mitigate the consequences of MI are a high priority. Cardiac progenitor cells (CPCs) have been used to treat cardiac injury post-MI, and despite poor engraftment, they have been shown to inhibit apoptosis and to promote angiogenesis through poorly understood paracrine effects. We previously reported that the direct injection of exosomes derived from CPCs (CPCexo) into mouse hearts provides protection against apoptosis in a model of acute ischemia/reperfusion injury. Moreover, we and others have reported that reactive oxygen species (ROS) derived from NADPH oxidase (NOX) can enhance angiogenesis in endothelial cells (ECs). Here we examined whether bioengineered CPCexo transfected with a pro-angiogenic miR-322 (CPCexo-322) can improve therapeutic efficacy in a mouse model of MI as compared to CPCexo. Systemic administration of CPCexo-322 in mice after ischemic injury provided greater protection post-MI than control CPCexo, in part, through enhanced angiogenesis in the border zones of infarcted hearts. Mechanistically, the treatment of cultured human ECs with CPCexo-322 resulted in a greater angiogenic response, as determined by increased EC migration and capillary tube formation via increased Nox2-derived ROS. Our study reveals that the engineering of CPCexo via microRNA (miR) programing can enhance angiogenesis, and this may be an effective therapeutic strategy for the treatment of ischemic cardiovascular diseases.

IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

2007 ◽  
Vol 293 (4) ◽  
pp. H2248-H2253 ◽  
Author(s):  
Nancy C. Moss ◽  
William E. Stansfield ◽  
Monte S. Willis ◽  
Ru-Hang Tang ◽  
Craig H. Selzman
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Nuclear Factor Κb ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Artery Ligation ◽  
Cardiac Morbidity

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-κB (NF-κB) has been implicated as a key mediator of reperfusion injury. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated IκBα and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-κB activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.

scholarly journals Clinical translation of myocardial conditioning

2018 ◽  
Vol 314 (6) ◽  
pp. H1225-H1252 ◽  
Author(s):  
Hans Erik Bøtker ◽  
Thomas Ravn Lassen ◽  
Nichlas Riise Jespersen
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Blood Flow ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Ischemia ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Flow Restriction

Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes.

scholarly journals CCR6 Deficiency Increases Infarct Size after Murine Acute Myocardial Infarction

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1532
Author(s):  
David Schumacher ◽  
Elisa A. Liehn ◽  
Anjana Singh ◽  
Adelina Curaj ◽  
Erwin Wijnands ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Bone Marrow ◽  
Coronary Artery ◽  
Reperfusion Injury ◽  
Bone Marrow Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Cardiac Damage

Ischemia-reperfusion injury after the reopening of an occluded coronary artery is a major cause of cardiac damage and inflammation after acute myocardial infarction. The chemokine axis CCL20-CCR6 is a key player in various inflammatory processes, including atherosclerosis; however, its role in ischemia-reperfusion injury has remained elusive. Therefore, to gain more insight into the role of the CCR6 in acute myocardial infarction, we have studied cardiac injury after transient ligation of the left anterior descending coronary artery followed by reperfusion in Ccr6-/- mice and their respective C57Bl/6 wild-type controls. Surprisingly, Ccr6-/- mice demonstrated significantly reduced cardiac function and increased infarct sizes after ischemia/reperfusion. This coincided with a significant increase in cardiac inflammation, characterized by an accumulation of neutrophils and inflammatory macrophage accumulation. Chimeras with a bone marrow deficiency of CCR6 mirrored this adverse Ccr6-/- phenotype, while cardiac injury was unchanged in chimeras with stromal CCR6 deficiency. This study demonstrates that CCR6-dependent (bone marrow) cells exert a protective role in myocardial infarction and subsequent ischemia-reperfusion injury, supporting the notion that augmenting CCR6-dependent immune mechanisms represents an interesting therapeutic target.

scholarly journals Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

2021 ◽  
Vol 10 (13) ◽  
pp. 2968
Author(s):  
Alessandro Bellis ◽  
Giuseppe Di Gioia ◽  
Ciro Mauro ◽  
Costantino Mancusi ◽  
Emanuele Barbato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Therapeutic Strategy ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Ischemic Time ◽  
St Elevation

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

Abstract 14834: Protective Role of Cardiomyocyte-derived Ddt in Ischemic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yina Ma ◽  
Xiaoyue Hu ◽  
Daniel Pfau ◽  
Xiaohong Wu ◽  
Veena Rao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Map Kinase ◽  
Ischemic Cardiomyopathy ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Lv Function ◽  
Acute Ischemia ◽  
S6 Kinase ◽  
Sham Surgery

Background: D-dopachrome tautomerase (DDT), the only homolog of macrophage migration inhibitory factor (MIF), is a cytokine highly expressed in cardiomyocytes and exerts autocrine-paracrine effects by signaling through the CD74 receptor. Endogenous DDT and MIF prevent acute ischemia-reperfusion injury and pressure overload-induced heart failure in mice. This study investigated whether endogenous cardiomyocyte DDT has a role in ischemic cardiomyopathy (ICM). Methods: LV tissue was obtained from patients with ICM during heart transplantation and from non-transplanted donor hearts. Plasma DDT concentrations were measured in heart failure outpatients with ICM. Cardiomyocyte-specific DDT knockout (cKO) and littermate control (CON) mice underwent MI or sham surgery. Serial echocardiography was performed to assess LV remodeling after MI or sham surgery. Tissue from the non-infarct region was analyzed 3 days and 4 weeks after MI or sham surgery for histology and molecular studies. Results: Cardiac DDT mRNA and protein expression were reduced in LV from patients transplanted for ICM (n=8). Plasma DDT concentrations below the median value were associated with worse survival in ICM outpatients (p<0.05, n=32). In mice, baseline LV function was similar in DDT cKO and CON after sham surgery and 3 days post-MI. However, DDT cKO mice developed more rapid LV dilatation and decreased LV ejection fraction and stroke volume as early as 1-week post-MI (n=4-6/group, all P<0.05). The DDT cKO mice had smaller cardiomyocyte cross-sectional area 4 weeks after MI (p <0.05), as well as early diminished phosphorylation of mTOR and S6-kinase (3 days post-MI). They also showed increased apoptosis 3 days post-MI and an early increase in p38 MAP kinase activation. Conclusion: Cardiomyocyte-derived DDT prevents adverse cardiac remodeling in ICM, potentially through modulating mTOR/S6 kinase (adaptive hypertrophy) and p38 MAP kinase (limiting apoptosis). Down-regulation of DDT in patients with ICM may contribute to the pathogenesis of advanced heart failure.

Abstract 13879: Ischemic Postconditioning Confers Cardioprotection through Adiponectin-dependent Mitochondrial STAT3 Activation in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Haobo Li ◽  
Michael G Irwin ◽  
Zhengyuan Xia
Keyword(s):  
Cell Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Systolic Pressure ◽  
Gene Knockdown ◽  
Area At Risk ◽  
In Cells

Introduction: Signal transducer and activator of transcription 3 (STAT3) plays a key role in postconditioning (IPo) mediated protection against myocardial ischemia reperfusion injury, but the mechanism by which IPo activates STAT3 is unknown. Adiponectin (APN), a protein with anti-ischemic properties, activates STAT3. We hypothesized that IPo activates mitochondrial STAT3 (MitoSTAT3) via APN signaling. Methods and Results: Wild type (WT) and APN knockout (KO) mice were either sham operated or subjected to 30 min of coronary artery occlusion followed by 2 hours of reperfusion with or without IPo (3 cycles of 10 seconds reperfusion and 10 seconds reocclusion; n=8/group). At the end of reperfusion, KO mice exhibited more severe myocardial injury evidenced as increased infarct size (% of area at risk) 49.2±2.0 vs WT 39.4±3.5, P <0.01; plasma troponin I (ng/ml): KO 72.8±7.6 vs WT 45.7±4.0, P <0.01; worse cardiac function (lower dP/dt max and end-systolic pressure-volume relation, P <0.05); more severely impaired mitochondrial function (reductions in complex IV and complex V protein expression) and more severe reduction of MitoSTAT3 phosphorylation (activation) at site Ser727, P <0.01. IPo significantly attenuated post-ischemic cardiac injury and dysfunction with a concomitant increase in phosphorylated MitoSTAT3 and attenuation of mitochondrial dysfunction in WT (all P <0.05) but not in KO mice. In cultured cardiac H9C2 cells, hypoxic postconditioning (HPo, 3 cycles of 5 min hypoxia and 5 min reoxygenation) significantly attenuated hypoxia/reoxygenation (HR, 3 hours hypoxia/3 hours reoxygenation) induced cell injury (increased apoptotic cell death as % of HR): HR 100.2±0.4 vs HPo 78.2±4.8, P <0.05) and reduced mitochondrial transmembrane potential (% total cells, HR 37.2±4.9 vs HPo 23.5±3.7, P <0.01). APN, adiponectin receptor 1 (AdipoR1), or STAT3 gene knockdown but not AdipoR2 gene knockdown, respectively, abolished HPo cellular protection (all P <0.05 vs. HPo). APN supplementation (10μg/ml) restored HPo protection in cells with APN knockdown but not in cells with AdipoR1or STAT3 gene knockdown. Conclusion: Adiponectin and AdipoR1 signaling are required for IPo to activate myocardial mitochondrial STAT3 to confer cardioprotection.

Zingerone Alleviates Myocardial Ischemia/Reperfusion Injury

2021 ◽  
Vol 19 (4) ◽  
pp. 543-549
Author(s):  
Fanglin Luo ◽  
Shunxiang Luo ◽  
Yanqing Wu
Keyword(s):  
Myocardial Infarction ◽  
Proinflammatory Cytokine ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Protective Effects ◽  
Cytokine Release ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Using a rat model, we have explored the underlying mechanism of ischemia/reperfusion (I/R)-mediated myocardial infarction and assessed the protective potential of zingerone. The results show that zingerone exhibits not only the myocardial protective effect, but also antioxidative and anti-inflammatory effects by suppression of markers of oxidation and proinflammatory cytokine release. Zingerone promotes protective effects against I/R-induced myocardial infarction by regulating Nrf2/HO-1 and NF-κB signaling pathways. These findings provide novel insights into the effects of zingerone on the cardioprotective mechanism of myocardial injury after I/R and may open new avenues for myocardial infarction treatment.

scholarly journals Diabetic Inhibition of Preconditioning- and Postconditioning-Mediated Myocardial Protection against Ischemia/Reperfusion Injury

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Xia Yin ◽  
Yang Zheng ◽  
Xujie Zhai ◽  
Xin Zhao ◽  
Lu Cai
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Protective Effect ◽  
Myocardial Protection ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Patients ◽  
Protective Mechanisms ◽  
Gsk 3Β ◽  
Pathogenic Effects

Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2–6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3β pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3β pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries.

scholarly journals The Protective Effect of Total Flavones from Rhododendron simsii Planch. on Myocardial Ischemia/Reperfusion Injury and Its Underlying Mechanism

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Sheng-Yong Luo ◽  
Qing-Hua Xu ◽  
Gong Peng ◽  
Zhi-Wu Chen
Keyword(s):  
Myocardial Infarction ◽  
Protective Effect ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Assay Method ◽  
Protective Effects ◽  
Rhododendron Simsii ◽  
Rhoa Activity ◽  
Protein Expressions

Objectives. Total flavones from Rhododendron simsii Planch. (TFR) are the effective part extracted from the flowers of Rhododendron simsii Planch. and have obvious protective effects against cerebral ischemic or myocardial injuries in rabbits and rats. However, their mechanism of cardioprotection is still unrevealed. Therefore, the present study was designed to investigate the effect of TFR on myocardial I/R injury and the underlying mechanism. Methods. TFR groups were treated by gavage once a day for 3 days at a dose of 20, 40, and 80 mg/kg, respectively, and then the model of myocardial I/R injury was established. Myocardial infarction, ST-segment elevation, and the expression of UTR, ROCK1, ROCK2, and p-MLC protein in rat myocardium were determined at 90 min after reperfusion. UTR siRNA in vivo transfection and competition binding assay method were used to study the relationship between the protective effect of TFR and UTR. Results. The expression of UTR protein markedly decreased in myocardium of UTR siRNA transfection group rats. TFR could significantly reduce the infarct size and inhibit the increase of RhoA activity and ROCK1, ROCK2, and p-MLC protein expressions both in WT and UTR knockdown rats. The reducing rate of TFR in myocardial infarction area, RhoA activity, and ROCK1, ROCK2, and p-MLC protein expressions in UTR knockdown rats decreased markedly compared with that in WT rats. In addition, TFR had no obvious effect on the increase of ΣST in UTR knockdown rats in comparison with that in model group. In particular, TFR could significantly inhibit the combination of [I125]-hu-II and UTR, and IC50 was 0.854 mg/l. Conclusions. The results indicate that the protective effect of TFR on I/R injury may be correlated with its blocking UTR and the subsequent inhibition of RhoA/ROCK signaling pathway.

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