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Project description:Nuclear receptor Reverb alpha is a component of circadian rythm which could be evolved in cardioprotection strategy. We test if pharmacological modulation of these target could be suitable for cardioprotection after ischemia reperfusion injury We used microarrays to detail the global programme of gene expression
2018-03-15 | GSE62458 | GEO
Project description:Heart expression data after short ischemia/reperfusion in WT, Reverb alpha KO and Reverb alpha antagonist-treated mice
| PRJNA264170 | ENA
Project description:Nuclear receptor Reverb alpha is a component of circadian rythm which could be evolved in cardioprotection strategy. We test if pharmacological modulation of these target could be suitable for cardioprotection after ischemia reperfusion injury We used microarrays to detail the global programme of gene expression
2018-03-15 | GSE62457 | GEO
Project description:We analyzed the lactylomes and proteomes of infarcted myocardium in mice subjected to sham treatment, myocardial infarction (MI) for 30 min or MI followed by I/R for 6 h using liquid chromatography-tandem mass spectrometry (LC–MS/MS) system.
2024-11-20 | PXD046631 | Pride
Project description:RATIONALE:Ischemic heart disease (IHD) is a leading cause of mortality. The most effective intervention for IHD is reperfusion, which ironically causes ischemia reperfusion (I/R) injury mainly due to oxidative stress-induced cardiomyocyte death. The exact mechanism and site of reactive oxygen species (ROS) generation during I/R injury remain elusive. OBJECTIVE:We aim to test the hypothesis that Complex I-mediated forward and reverse electron flows are the major source of ROS in I/R injury of the heart. METHODS AND RESULTS:We used a genetic model of mitochondrial Complex I deficiency, in which a Complex I assembling subunit, Ndufs4 was knocked out in the heart (Ndufs4H-/-). The Langendorff perfused Ndufs4H-/- hearts exhibited significantly reduced infarct size (45.3?±?5.5% in wild type vs 20.9?±?8.1% in Ndufs4H-/-), recovered contractile function, and maintained mitochondrial membrane potential after no flow ischemia and subsequent reperfusion. In cultured adult cardiomyocytes from Ndufs4H-/- mice, I/R mimetic treatments caused minimal cell death. Reintroducing Ndufs4 in Ndufs4H-/- cardiomyocytes abolished the protection. Mitochondrial NADH declined much slower in Ndufs4H-/- cardiomyocytes during reperfusion suggesting decreased forward electron flow. Mitochondrial flashes, a marker for mitochondrial respiration, were inhibited in Ndufs4H-/- cardiomyocytes at baseline and during I/R, which was accompanied by preserved aconitase activity suggesting lack of oxidative damage. Finally, pharmacological blockade of forward and reverse electron flow at Complex I inhibited I/R-induced cell death. CONCLUSIONS:These results provide the first genetic evidence supporting the central role of mitochondrial Complex I in I/R injury of mouse heart. The study also suggests that both forward and reverse electron flows underlie oxidative cardiomyocyte death during reperfusion.
| S-EPMC6192835 | biostudies-literature
Project description:The small GTPase RhoA serves as a nodal point for signaling through hormones and mechanical stretch. However, the role of RhoA signaling in cardiac pathophysiology is poorly understood. To address this issue, we generated mice with cardiomyocyte-specific conditional expression of low levels of activated RhoA (CA-RhoA mice) and demonstrated that they exhibited no overt cardiomyopathy. When challenged by in vivo or ex vivo ischemia/reperfusion (I/R), however, the CA-RhoA mice exhibited strikingly increased tolerance to injury, which was manifest as reduced myocardial lactate dehydrogenase (LDH) release and infarct size and improved contractile function. PKD was robustly activated in CA-RhoA hearts. The cardioprotection afforded by RhoA was reversed by PKD inhibition. The hypothesis that activated RhoA and PKD serve protective physiological functions during I/R was supported by several lines of evidence. In WT mice, both RhoA and PKD were rapidly activated during I/R, and blocking PKD augmented I/R injury. In addition, cardiac-specific RhoA-knockout mice showed reduced PKD activation after I/R and strikingly decreased tolerance to I/R injury, as shown by increased infarct size and LDH release. Collectively, our findings provide strong support for the concept that RhoA signaling in adult cardiomyocytes promotes survival. They also reveal unexpected roles for PKD as a downstream mediator of RhoA and in cardioprotection against I/R.
| S-EPMC3148727 | biostudies-literature
Project description:Myocardial Ischemia-reperfusion injury is a serious clinical problem that lacks effective therapy.However, the precise mechanism leading to myocardial I/R injury remains unclear.Our study defined the dynamic changes of the differentially expressed genes related myocardial I/R injury, and provide basis for comprehensive understanding of the disease at molecular level. We investigated schemia-reperfusion –mediated gene expression alteration associated with the development of cardiac injury by microarray in a mouse model.
2020-10-31 | GSE160516 | GEO
Project description:IntroductionInsulin has shown antioxidation and cytoprotective effects to decrease heart ischemia/reperfusion injury (HI/RI) in diabetes mellitus (DM), but the role of insulin/poly(ethylene glycol)-carboxymethyl chitosan (PEG-CMCS) on HI/RI in DM is not known. This research explored whether insulin/PEG-CMCS revealed a protective effect on HI/RI in DM through ornithine decarboxylase (ODC)/polyamine systems.Materials and methodsDiabetes was induced via streptozotocin (STZ) in Sprague Dawley (SD) rats, which suffered from HI via blocking the left circumflex artery for 45 minutes, followed by 2 hours of reperfusion. α-Difluoromethylornithine-ethylglyoxal bis (guanylhydrazone) (DFMO-EGBG) and insulin/PEG-CMCS were administered to diabetic rats to explore their roles on severity of HI/RI.ResultsInsulin could be fleetly and efficiently loaded via the nanocarrier PEG-CMCS at pH =6, showing efficient loading and stable release. In addition, insulin/PEG-CMCS showed significant hypoglycemic activity in diabetic rats. On the other hand, ischemia/reperfusion obviously augmented the contents of creatine kinase (CK), lactic dehydrogenase (LDH), putrescine (Pu), myocardial infarct size, and NF-κB and spermidine/spermine N'-acetyltransferase (SSAT) expressions and decreased the levels of spermine (Sp), polyamine pools (PAs), heart rate (HR), coronary blood flow (CF), left ventricular developed pressure (LVDP), and ODC expression, compared with Sham. Administration of insulin and insulin/PEG-CMCS both reduced the contents of CK, LDH, Pu, myocardial infarct size, and NF-κB and SSAT expressions and increased the levels of Sp, PAs, HR, CF, LVDP, and ODC expression, while insulin/PEG-CMCS significantly indicated the protective results, and DFMO-EGBG showed the opposite effects.ConclusionThe research showed that insulin/PEG-CMCS could play a protective effect on HR/RI in diabetic rats via its antioxidative, antiapoptotic, and anti-inflammatory roles and modulating ODC/polyamine systems.
| S-EPMC5922236 | biostudies-literature
Project description:BackgroundSilent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R).Methods and resultsProtein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1(-/-) mice exhibited a significant increase (44±5% versus 15±5%; P=0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15±4% versus 36±8%; P=0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei (4±3% versus 10±1%; P<0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvival molecules, including manganese superoxide dismutase, thioredoxin-1, and Bcl-xL, whereas it negatively regulates the proapoptotic molecules Bax and cleaved caspase-3. The level of oxidative stress after I/R, as evaluated by anti-8-hydroxydeoxyguanosine staining, was negatively regulated by Sirt1. Sirt1 stimulates the transcriptional activity of FoxO1, which in turn plays an essential role in mediating Sirt1-induced upregulation of manganese superoxide dismutase and suppression of oxidative stress in cardiac myocytes. Sirt1 plays an important role in mediating I/R-induced increases in the nuclear localization of FoxO1 in vivo.ConclusionsThese results suggest that Sirt1 protects the heart from I/R injury through upregulation of antioxidants and downregulation of proapoptotic molecules through activation of FoxO and decreases in oxidative stress.
| S-EPMC3003297 | biostudies-literature
Project description:Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency. Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (I/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress. Results: No structural changes (echocardiogram) or coronary flow/left ventricle pressure (isolated hearts) were observed in TERT-/- rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT-/- compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated (n = 6 in each group; p < 0.05) in the TERT-/-. Interestingly, infarct size was less in TERT-/- rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT-/- compared to WT. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT-/- compared to the WT. Conclusion: Absence of TERT activity increases susceptibility to stress like cardiac injury. These results suggest a critical role of telomerase in chronic heart disease.
| S-EPMC6454001 | biostudies-literature