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At least 19 recordsLinked to original sources
PubMed1977

Studies on myocardial reperfusion injury. I. Favorable modification by adjusting reperfusate pH.

This study tests the hypothesis that postischemic myocardial depression can be reduced by providing an initial reperfusate pH which is appropriate for myocardial temperature (i.e., metabolic systems function optimally when pH is kept slightly alkaline to the neutral point, which changes with temperature in concordance with the pK of water). Ten dogs underwent 1 hour of ischemic arrest with topical hypothermia (intramyocardial temperature 16+/-2 degrees C). The initial reperfusate (500 cc of blood from the extracorporeal circuit) was infused (100 cc/minute) into the proximal aorta just before removing the cross-clamp. Reperfusate pH was kept at 7.4 in five dogs (control) and raised to 7.8 with THAM [tris (hydroxymethyl) aminomethane] in five dogs. Measurements 30 minutes after reperfusion showed that raising reperfusate pH to 7.8 resulted in (1) higher subendocardial blood flows (109+/-20 vs 61 cc+/-8 cc/100 gm/minute), (2) redistribution of postischemic blood flow toward the subendocardium (endocardial/epicardial flow 1.25+/-0.1 vs 1.0+/-0.03), (3) higher left ventricular oxygen uptakes (0.046 vs 0.033 cc/100 gm/beat), (4) better postischemic left ventricular compliance (56+/-3% more compliant), and (5) improved left ventricular performance (88+/-7% recovery vs only 57+/-3% recovery at pH 7.4). Postischemic edema (2% water gain) was unchanged by pH modification. We conclude that initial reperfusion with the appropriate pH provides an optimal milieu for restoration of cellular metabolism, counteracts the acidosis of ischemia, and improves postischemic left ventricular blood flow, distribution, oxygen uptake, compliance, and performance.

Animals↗
PubMed2025

Suppression of OTUD4 protects against myocardial ischemia-reperfusion injury by increasing autophagic flux and inhibiting apoptosis in cardiomyocytes.

Dysregulated autophagic flux plays a critical role in myocardial ischemia-reperfusion injury (MIRI), complicating cardiac reperfusion therapy. In this study, we identified OTUD4 as a potential regulator of autophagic flux in MIRI using CRISPR/Cas9 sgRNA sequencing. However, the underlying mechanism is poorly understood. The purpose of this study is to investigate the effects of OTUD4 on autophagic flux in OGD-R treated AC16 cells (IRI model in vitro) and LAD artery ligation induced myocardial ischemia-reperfusion mice (MIRI model in vivo). In the in vitro IRI cell model, OTUD4 knockdown significantly reversed impaired autophagic flux, increased mitochondrial membrane potential, and decreased LDH activity, ROS production, autophagy and apoptosis. Overexpression of OTUD4 showed the opposite result. In the in vivo MIRI model, OTUD4 knockdown also significantly decreased infarct area, improved cardiac structure and function, reduced serum BNP and LDH levels, attenuated cardiac tissue injury/fibrosis/myocardial hypertrophy, and ultimately exerted myocardial protective effects against ischemia-reperfusion injury. Importantly, OTUD4 knockdown inhibited autophagosome-associated markers (LC3II/LC3I, Beclin1, ATG9), autophagy substrate p62, increased lysosomal activity marker LAMP2, and activated the autophagy pathway (AKT/mTOR), thereby promoting the recovery of impaired autophagic flux in the MIRI model. Moreover, OTUD4 showed strong interaction with UBAC1, and OTUD4 deficiency decreases UBAC1 protein expression by impairing its deubiquitination, thereby regulating autophagy. In short, blocking OTUD4 restored damaged autophagic flux in I/R induced myocardial injury both in vivo and in vitro, inhibited myocardial cell apoptosis, and greatly improved cardiac function in ischemia-reperfusion mice. KEY MESSAGES: OTUD4 was identified as a key negative regulator of autophagy flux in myocardial ischemia-reperfusion injury (MIRI) via genome-wide CRISPR/Cas9 screening. OTUD4 knockdown exerts cardioprotective effects by reducing apoptosis and ROS generation and improving heart function in both in vitro and in vivo models. The interaction between OTUD4 and UBAC1 was confirmed, and OTUD4 maintains UBAC1 stability through deubiquitination, providing new insights into the ubiquitination regulatory mechanism in myocardial injury. Targeting OTUD4 has therapeutic potential for MIRI, as OTUD4 knockdown alleviated MIRI in both in vitro and in vivo models, suggesting the possibility of developing OTUD4 inhibitors for cardiac reperfusion treatment.

Animals↗
PubMed2026

MLL4 protects cardiomyocytes against ischemia-reperfusion injury through STAT3-mediated mitochondrial function.

Myocardial ischemia-reperfusion injury (MIRI) is an inevitable pathophysiological response during the revascularization process following myocardial ischemia. Despite its clinical significance, effective targeted therapies for MIRI remain an unmet medical need. Mixed-lineage leukemia 4 (MLL4), a member of the SET family of histone methyltransferases, exhibits particular methyltransferase action toward histone H3 lysine 4 (H3K4). This study establishes a protective role for MLL4 in MIRI pathogenesis. Utilizing cardiomyocyte-specific Mll4 knockout mice and an in vivo ischemia-reperfusion (I/R) model induced by left anterior descending coronary artery ligation, we observed significant upregulation of MLL4 expression in cardiac tissue following I/R. Genetic ablation of Mll4 in cardiomyocytes markedly exacerbated both acute and chronic phases of MIRI. In vitro, Mll4 knockdown in neonatal rat cardiomyocytes (NRCMs) amplified mitochondrial dysfunction and apoptosis under hypoxia/reoxygenation (H/R) conditions. Integrated analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) revealed that Mll4 deficiency induces a pronounced reduction in H3K4 monomethylation (H3K4me1) and histone H3 lysine 27 acetylation (H3K27ac) enrichment at the Stat3 genomic locus. Mechanistically, MLL4 functions as a transcriptional activator of Stat3 by depositing H3K4me1 and H3K27ac, thereby facilitating STAT3 transcription. This regulatory cascade ultimately governs STAT3-dependent mitochondrial homeostasis. Collectively, these findings identify MLL4 as a critical epigenetic regulator of MIRI and suggest its therapeutic targeting may offer a promising strategy for mitigating reperfusion injury.

Animals↗
PubMed2026

Development of Electrocardiography Standards for Evaluating Myocardial Infarction and Ischemia-Reperfusion Injury in Mice.

BACKGROUND: Acute and chronic heart failure secondary to myocardial infarction (MI) and cardiac ischemia-reperfusion injury (IRI) are leading causes of death in ischemic heart disease. A mouse model is indispensable for investigating MI and IRI, and the development of reliable mouse MI and IRI models is essential for advancing research in this field. The clear early diagnostic criteria for confirming successful induction of MI and IRI in mice remain lacking. METHODS: Adult C57BL/6J background mice underwent left anterior descending coronary artery ligation to induce acute MI, or ligation followed by reperfusion to induce IRI. The success of the MI and IRI model establishment was confirmed by 2,3,5-triphenyltetrazolium chloride staining and echocardiography. Electrocardiography was used to monitor the electric activity in the mice. CONCLUSIONS: Electrocardiography demonstrated that ST-segment elevation in ECG lead II and corrected QTc interval prolongation at 30 minutes following left anterior descending ligation as 2 key early indicators of successful MI. Echocardiography analysis revealed that the magnitude of ST-segment elevation strongly correlated with the left anterior descending ligation site, where a more proximal ligation produced a greater ST-segment elevation amplitude and more severe ischemia. In IRI models, ST-segment elevation typically resolved and returned to baseline within 20 minutes of reperfusion. This study developed quantifiable early diagnostic criteria for successful MI and IRI induction based on characteristic ECG changes. These quantifiable ECG parameters provide early diagnostic standards that can significantly streamline and optimize modeling procedures.

Animals↗
PubMed2026

Transcription Factor SP1 Drives Myocardial Ischemia/reperfusion Injury By Transcription Activation-mediated GADD45G Upregulation.

Myocardial ischemia-reperfusion injury (MIRI) is an unresolved clinically fatal complication in the management of acute myocardial infarction (AMI). Growth arrest and DNA damage-inducible gene 45 Gamma (GADD45G) plays a vital role in the regulation of MIRI. However, the underlying mechanisms remain unclear. GADD45G and SP1 expression were upregulated in hypoxia/reoxygenation (H/R)-treated H9C2 cells. H/R treatment repressed H9C2 cell viability, and induced apoptosis, oxidative stress, and inflammatory response. Moreover, GADD45G deficiency could relieve H/R-triggered H9C2 cell injury. In mechanism, SP1 was a transcription factor of GADD45G and activated the transcription of GADD45G via binding to its promoter region. Besides, SP1 knockdown alleviated MI/R-induced pathological damage in the myocardial tissue of rats by regulating GADD45G. In conclusion, SP1 could promote H/R-induced cardiomyocyte injury and MI/R-caused rat myocardial tissue pathological injury by increasing GADD45G, providing a promising therapeutic target for MIRI treatment.

Animals↗
PubMed2026

Perm1 enhances Nrf2-driven antioxidant defense through Keap1 oxidation during myocardial ischemia/reperfusion injury.

Ischemia/reperfusion (IR) enhances oxidative stress, leading to myocardial injury. Although Perm1 promotes cytoprotective mechanisms, the underlying mechanisms are poorly understood. Cysteine oxidation of Keap1 alleviates Cul3-mediated ubiquitination/degradation of Nrf2 and promotes antioxidant transcription. Here we show that Perm1 activates Nrf2 through cysteine oxidation of Keap1 and stabilization of Nrf2. Endogenous Perm1 was downregulated during IR, whereas the rescue of Perm1 reduced IR injury. Downregulation of Perm1 exacerbated oxidative stress, whereas upregulation of Perm1 alleviated it, accompanied by downregulation and upregulation of Nrf2-regulated antioxidant genes, respectively. Perm1 promoted oxidation of cysteine residues in Keap1, possibly through thiol-disulfide exchange reactions, which decreases Keap1-Nrf2 interaction and inhibits Cul3-mediated degradation of Nrf2. We identified Cys121 and Cys746 in Perm1 as critical for Keap1 oxidation and cardioprotection. Thus, Perm1 induces cysteine oxidation of Keap1, thereby conferring myocardial resistance to IR injury by inducing Nrf2 stabilization and transcriptional activation of antioxidant genes.

Kelch-Like ECH-Associated Protein 1↗
PubMed1977

Myocardial consequences of coronary artery bypass graft surgery. The paradox of necrosis in areas of revascularization.

Myocardial infarction after coronary artery bypass graft (CABG) surgery has been described clinically in up to 30% of patients but there is little morphologic information about the character and pathogenesis of the myocardial injury. We studied myocardium in the distribution of bypassed and nonbypassed coronary arteries for the presence of contraction band necrosis as compared to coagulation necrosis, in 58 autopsied patients who died less than 1 month after surgery. Operation related necrosis consisting of focal subendocardial contraction band necrosis was present to some degree in 48 (83%) patients. Regional transmural necrosis was present in 22 (38%) patients and was of two types. Contraction band necrosis occurred in 18 patients and was in the distribution of a patent bypassed coronary artery in 15 of them. Coagulation necrosis was found in four patients, and in each was in the distribution of a new graft-releated coronary artery occlusion. The results suggest that coronary artery reflow through widely patent grafts following the period of operative nonperfusion, rather than graft or intrinsic coronary artery occlusion, accounts for the majority of operation-related myocardial "infarcts" associated with CABG surgery. Thus, prevention of intraoperative myocardial injury must also focus on characteristics of the phase of myocardial reperfusion.

Adult↗
PubMed2026

Intravenous Nicorandil in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary PCI: The CLEAN Randomized Clinical Trial.

BACKGROUND: Nicorandil, an adenosine triphosphate-sensitive potassium-channel opener with nitrate-like properties, may reduce reperfusion injury and microvascular obstruction in ST-segment elevation myocardial infarction (STEMI), but large-scale randomized evidence on long-term clinical outcomes is inconclusive. OBJECTIVES: The CLEAN trial aimed to assess whether adjunctive intravenous nicorandil improves 12-month clinical outcomes in patients with STEMI undergoing primary percutaneous coronary intervention. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial conducted at 49 hospitals in China, patients aged 18 to 80 years with STEMI within 12 hours of symptom onset were randomly assigned (1:1) to receive intravenous nicorandil (6 mg bolus before reperfusion followed by 6 mg/h infusion for 48 h) or matching placebo. Oral nicorandil was prohibited during follow-up. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, or unplanned hospitalization for heart failure within 12 months. RESULTS: Between January 2021 and December 2023, 1,503 patients were enrolled and randomly assigned to nicorandil (n = 748) or placebo (n = 755). The primary composite outcome occurred in 98 patients (13.1%) in the nicorandil group (113 events over 717.2 person-years) and 99 (13.1%) in the placebo group (136 events over 710.3 person-years), with no significant difference between groups (rate ratio: 0.869; 95% CI: 0.650-1.162; P = 0.3429). Among secondary outcomes, nominal reductions were observed in cardiovascular death (1.9% vs 3.6%; HR: 0.515; 95% CI: 0.269-0.983) and target-vessel revascularization (1.1% vs 3.0%; HR: 0.322; 95% CI: 0.143-0.727), whereas rates of nonfatal myocardial infarction and unplanned hospitalization for heart failure were similar between groups. Adverse events did not differ between groups. CONCLUSIONS: In patients with STEMI undergoing primary percutaneous coronary intervention, adjunctive intravenous nicorandil did not significantly reduce the 12-month primary composite outcome. These findings do not support routine use of intravenous nicorandil in unselected patients with STEMI. (Clinical Efficacy and sAfety of Intravenous Nicorandil; NCT04665648).

Humans↗
PubMedDate not supplied

Tolerance to ischemia in the human heart.

The tolerance to ischemic cardiac arrest during open-heart surgery depends on the degree of hypertrophy and on the functional impairment of the heart. The angiographically determined muscle mass is a good indicator of the susceptibility of the myocardium to ischemic injury and of its ability to quickly restore myocardial structure upon reperfusion. Tissue from extremely hypertrophied hearts exhibited numerous degenerative alterations.

Adult↗
PubMed1979

Nifedipine: a myocardial protective agent.

The effectiveness of the calcium antagonist nifedipine in preserving postischemic myocardial function and structural integrity was experimentally demonstrated in isolated rabbit hearts, in conscious dogs subjected to myocardial infarction, in open chest anesthetized dogs with normothermic regional ischemia induced for 1 to 2 hours and in dogs undergoing hypothermic global ischemia for 2 hours followed by 2 hours of reperfusion. Nifedipine had a beneficial effect on postischemic myocardial stiffness and mitochondrial calcium accumulation, which were correlated. Administration of nifedipine at the onset of myocardial infarction increased blood flow to ischemic zones of myocardial infarction and resulted in less loss of creatine kinase. It reduced by two- to three-fold the volume of the ischemia-reperfusion injury induced by left anterior descending coronary arterial occlusion and release and preserved indexes of hemodynamic function. Nifedipine was found effective in protecting myocardial performance and structure after 2 hours of global ischemia during hypothermic cardiopulmonary bypass. It is suggested that this agent may be useful as an adjunct to cold cardioplegia in man for enhanced myocardial protection during cardiac surgery.

Animals↗
PubMed1979

Experimental evaluation of hypothermic intermittent coronary perfusion.

The recovery of the myocardial contractility of blood-perfused papillary muscle from the rabbit hearts was used to determine if hypothermia would minimize the myocardial injury associated with intermittent aortic cross-clamping (IACC). Continuous normothermic coronary perfusion for 2 hours with either cross circulation or a membrane oxygenator had only minimal adverse effects on contractility. None of the hearts tolerated normothermic IACC (45 minutes of anoxia and 10 minutes of reperfusion, repeated twice), When the myocardial temperature was reduced to 32 degrees C., the recovery following IACC was 41.25 +/- 11.21 percent (n=8). With hypothermia of 28 degrees C., it was 70.43 +/- 13.03 percent (cross circulation group, n=7) or 68.36 +/- 13.11 percent (membrane oxygenator group, n=7). If the hearts were cooled to 24 degrees C., the recovery of the myocardial contractility following IACC was 90.95 +/- 5.42 percent (n=11). The improvement of the degree of recovery by hypothermia was statistically highly significant (p less than 0.005). Creatine phosphokinase (CPK) and isoenzymes (CPK-MB) were also measured in some groups, but the results warrrant further studies before they can be correlated with the myocardial function.

Animals↗
PubMed1979

Potassium-induced cardioplegia during normothermic cardiac arrest. Morphologic study of the effect of varying concentrations of potassium on myocardial anoxic injury.

Most corrective procedures as well as myocardial revascularization require a period of cardiac arrest, and numerous methods have been proposed to protect the myocardium during this ischemic episode. Potassium-induced cardioplegia is one method that appears to be of benefit in this setting. Since it is recognized that myocardial necrosis may result at very high doses of potassium, we examined the effect of varying concentrations of potassium on myocardial anoxic injury. Using an isolated rat heart preparation, we evaluated anoxic injury occurring with cardioplegic solutions containing various concentrations of K+, ranging from 15 to 200 mEq. per liter, during a 50 minute normothermic arrest followed by 60 minutes of reperfusion. The transverse histologic sections of the left ventricular myocardium were analyzed for contraction band injury by morphometric and qualitative methods. Among the 62 animals studied the least severe anoxic injury was seen with K+ cardioplegia at concentrations of 25 and 30 mEq. per liter. At lower and higher concentrations there was little difference between the hearts exposed to anoxia with or without K+ cardioplegia. Potassium administered in very high doses, i.e., 100 or 200 mEq. of K+ per liter, led to contracture and extensive myocardial cell injury. This study suggests that potassium-induced cardioplegia is effective in reducing cell injury due to anoxia, and in this model an optimal concentration range was 25 to 30 mEq. per liter.

Animals↗