scholarly journals Myocardial Ischemia-Reperfusion and Diabetes: Lessons Learned From Bedside to Bench

2021 ◽  
Vol 8 ◽  
Author(s):  
Maya Dia ◽  
Alexandre Paccalet ◽  
Bruno Pillot ◽  
Christelle Leon ◽  
Michel Ovize ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Animal Models ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Diabetic Patients ◽  
Myocardial Ischemia Reperfusion ◽  
Hypoxia Reoxygenation

In front of the failure to translate from bench to bedside cardioprotective drugs against myocardial ischemia-reperfusion, research scientists are currently revising their animal models. Owing to its growing incidence nowadays, type 2 diabetes (T2D) represents one of the main risk factors of co-morbidities in myocardial infarction. However, discrepancies exist between reported animal and human studies. Our aim was here to compare the impact of diabetes on cell death after cardiac ischemia-reperfusion in a human cohort of ST-elevation myocardial infarction (STEMI) patients with a diet-induced mouse model of T2D, using a high-fat high-sucrose diet for 16 weeks (HFHSD). Interestingly, a small fraction (<14%) of patients undergoing a myocardial infarct were diabetic, but treated, and did not show a bigger infarct size when compared to non-diabetic patients. On the contrary, HFHSD mice displayed an increased infarct size after an in vivo cardiac ischemia-reperfusion, together with an increased cell death after an in vitro hypoxia-reoxygenation on isolated cardiomyocytes. To mimic the diabetic patients' medication profile, 6 weeks of oral gavage with Metformin was performed in the HFHSD mouse group. Metformin treatment of the HFHSD mice led to a similar extent of lower cell death after hypoxia-reoxygenation as in the standard diet group, compared to the HFHSD cardiomyocytes. Altogether, our data highlight that due to their potential protective effect, anti-diabetic medications should be included in pre-clinical study of cardioprotective approaches. Moreover, since diabetic patients represent only a minor fraction of the STEMI patients, diabetic animal models may not be the most suitable translatable model to humans, unlike aging that appears as a common feature of all infarcted patients.

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.

scholarly journals Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice

2011 ◽  
Vol 301 (3) ◽  
pp. E447-E455 ◽  
Author(s):  
Yanzhuo Ma ◽  
Yi Liu ◽  
Shaowei Liu ◽  
Yan Qu ◽  
Rutao Wang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Dynamic Change ◽  
Receptor Expression ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Myocardial Ischemia Reperfusion ◽  
Underlying Mechanisms

The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients.

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.

scholarly journals Downregulated LINC01614 Ameliorates Hypoxia/Reoxygenation-Stimulated Myocardial Injury by Directly Sponging microRNA-138-5p

Dose-Response ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 155932582091378 ◽  
Author(s):  
Jie Yang ◽  
Xue-Song Yang ◽  
Qian Zhang ◽  
Xin Zhuang ◽  
Xiao-Kang Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Gene Expression Omnibus ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Myocardial Ischemia Reperfusion ◽  
Dual Luciferase Reporter Assay ◽  
Hypoxia Reoxygenation

Background: LINC01614 was abnormally expressed in myocardial infarction and other heart failures. We attempted to detect the effects of LINC01614 in myocardial ischemia–reperfusion (I/R) injury. Methods: H9c2 cardiomyocyte cells were treated with hypoxia/reoxygenation (H/R) to establish myocardial ischemia (MI) model. Results: Clinical data of Gene Expression Omnibus (GEO) database indicated that LINC01614 was highly regulated in first acute myocardial infarction, whereas miR-138-5p was downregulated in unstable angina pectoris. LINC01614 inhibition promoted cell proliferation and repressed the apoptotic property after H/R treatment using Cell Counting Kit-8 and flow cytometry analysis. Downregulation of LINC01614 enhanced the expression of Bcl-2 but attenuated Bax and cleaved caspase 3 expression after H/R treatment. Bioinformatics prediction and dual-luciferase reporter assay determined that LINC01614 directly targeted miR-138-5p and negatively regulated the expression of miR-138-5p. Furthermore, the overexpression of miR-138-5p significantly strengthened the function of si-LINC01614 in H/R groups. Conclusion: Our results illustrated that reduction in LINC01614 attenuated H/R treatment-induced myocardial damage via sponging miR-138-5p.

Abstract 027: Therapeutic Potential of a Novel Necrosis Inhibitor in Myocardial Ischemia-Reperfusion Injury

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Hyun-Jai Cho ◽  
In-Chang Hwang ◽  
Ju-Young Kim ◽  
Ji-Hyun Kim ◽  
Yoo-Wook Kwon ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Membrane Potential ◽  
Myocardial Ischemia ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Ischemia Reperfusion ◽  
In Vivo Models ◽  
Rat Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion

Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarction, paradoxically causes a wide variety of injuries. The opening of the mitochondrial permeability pore and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. Objectives: Necrosis, the main mechanism of cell death during I/R injury to the myocardium, is an uncontrolled cell death, a pathologic condition accompanying inflammatory responses. We aimed to examine the protective role of this novel necrosis inhibitor against myocardial I/R injury using in vitro and in vivo models through anti-necrosis pathway. Methods and Results: Rat cardiomyocytes were exposed to hypoxia-reoxygenation injury after pretreatment with dimethyl sulfoxide (vehicle), necrosis inhibitor (NecX), antioxidant (vitamin C) or apoptosis inhibitor (Z-VAD-fmk). NecX-treated cells, compared with vehicle, showed fewer necrosis (Annexin-V/PI) (13.5±1.9% versus 44.1±3.1%; P=0.049) and more viable cells (fluorescein diacetate) (98.0±0.5% versus 51.3±2.1%; P=0.021). We next analyzed the mechanisms of cell death, mitochondrial membrane potential and mitochondrial Ca 2+ level. NecX-treated group showed higher mitochondrial membrane potential and lower Ca 2+ level, resulting in the prevention of mitochondrial swelling and necrosis. In the rat model of myocardial ischemia for 45 minutes followed by reperfusion, we compared the therapeutic efficacy of NecX and cyclosporine A (CsA) with 5% dextrose (control), each administrated 5 minutes before reperfusion. Pretreatment with NecX markedly inhibited myocardial necrosis (NecX, 7.8±7.8%; control, 65.4±2.4%, P=0.017; CsA, 32.3±5.1%, P=0.041) and reduced the area of fibrosis (NecX, 4.8±0.9%; control, 25.7±1.6%, P=0.011; CsA, 18.8±1.3%, P=0.006). Additionally, it preserved systolic function and prevented pathologic remodeling of left ventricle. Conclusion: The novel necrosis inhibitor demonstrates a significant protective effect against myocardial I/R injury and has advantages over CsA, based more on the direct necrosis inhibition on cardiomyocytes, indicating that it is a promising candidate for cardioprotective adjunctive therapy with reperfusion in patients with myocardial infarction.

Abstract 6: ADAMTS13 Reduces VWF-Mediated Acute Myocardial Ischemia/Reperfusion Injury in Mice

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Chintan Gandhi ◽  
Steven Lentz ◽  
Anil Chauhan
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Myocardial Ischemia ◽  
Blocking Antibody ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Background and objective: ADAMTS13 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 implicate elevated VWF levels and reduced ADAMTS13 activity in plasma as risk factors for myocardial infarction, but it remains unknown whether the ADAMTS13/VWF axis contributes to myocardial infarction pathogenesis. We tested the hypothesis that ADAMTS13 reduces VWF-mediated myocardial ischemia/reperfusion 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. Results: Adamts13 -/- mice had significantly larger infarcts (mean ± SEM: 21.4 ± 1.3%, P <0.05) than WT mice (16.9 ± 1.2%) after myocardial ischemia/reperfusion injury. Adamts13+/- mice, which have a 50% reduction in ADAMTS13 activity, had similar sized infarcts (16.6 ± 1.3%) compared to those in 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. To test this hypothesis, we used a VWF-blocking antibody. Interestingly, WT mice treated with the VWF-blocking antibody showed a marked reduction in infarct size (7.9 ± 0.6%, P < 0.001) compared with WT mice treated with control Ig (17.5 ± 1.5 %). Finally, Adamts13 -/- mice treated with the VWF-blocking antibody had infarct sizes (8.0 ± 1.5%) that were similar to those WT mice treated with VWF-blocking antibody, demonstrating that increased infarct size in the Adamts13 -/- mice in this acute myocardial ischemia/reperfusion injury model is VWF-dependent. Conclusion: These findings reveal a new role for anti-thrombotic enzyme ADAMTS13 in reducing VWF-mediated myocardial ischemia/reperfusion injury.

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.

scholarly journals ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice

Blood ◽  
2012 ◽  
Vol 120 (26) ◽  
pp. 5224-5230 ◽  
Author(s):  
Chintan Gandhi ◽  
David G. Motto ◽  
Melissa Jensen ◽  
Steven R. Lentz ◽  
Anil K. Chauhan
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Acute Myocardial Ischemia ◽  
Adamts13 Deficiency ◽  
Myocyte Apoptosis ◽  
Myocardial Ischemia Reperfusion

Abstract Epidemiologic studies suggest that elevated VWF levels and reduced ADAMTS13 activity in the plasma are risk factors for myocardial infarction. However, it remains unknown whether the ADAMTS13-VWF axis plays a causal role in the pathophysiology of myocardial infarction. In the present study, we tested the hypothesis that ADAMTS13 reduces VWF-mediated acute myocardial ischemia/reperfusion (I/R) injury in mice. Infarct size, neutrophil infiltration, and myocyte apoptosis in the left ventricular area were quantified after 30 minutes of ischemia and 23.5 hours of reperfusion injury. Adamts13−/− mice exhibited significantly larger infarcts concordant with increased neutrophil infiltration and myocyte apoptosis compared with wild-type (WT) mice. In contrast, 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. Treating WT or Adamts13−/− mice with neutralizing Abs to VWF significantly reduced infarct size compared with control Ig–treated mice. 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. These findings reveal that ADAMTS13 and VWF are causally involved in myocardial I/R injury.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

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