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Journal of Cardiovascular Pharmacology... Nov 2021Vascular stiffness and endothelial dysfunction are accelerated by acute myocardial infarction (AMI) and subsequently increase the risk for recurrent coronary events.
BACKGROUND
Vascular stiffness and endothelial dysfunction are accelerated by acute myocardial infarction (AMI) and subsequently increase the risk for recurrent coronary events.
AIM
To explore whether remote ischemic perconditioning (RIPerc) protects against coronary and aorta endothelial dysfunction as well as aortic stiffness following AMI.
METHODS
Male OFA-1 rats were subjected to 30 min of occlusion of the left anterior descending artery (LAD) followed by reperfusion either 3 or 28 days with or without RIPerc. Three groups: (1) sham operated (Sham, without LAD occlusion); (2) myocardial ischemia and reperfusion (MIR) and (3) MIR + RIPerc group with 3 cycles of 5 minutes of IR on hindlimb performed during myocardial ischemia were used. Assessment of vascular reactivity in isolated septal coronary arteries (non-occluded) and aortic rings as well as aortic stiffness was assessed by wire myography either 3 or 28 days after AMI, respectively. Markers of pro-inflammatory cytokines, adhesion molecules were assessed by RT-qPCR and ELISA.
RESULTS
MIR promotes impaired endothelial-dependent relaxation in septal coronary artery segments, increased aortic stiffness and adverse left ventricular remodeling. These changes were markedly attenuated in rats treated with RIPerc and associated with a significant decline in P-selectin, IL-6 and TNF-α expression either in infarcted or non-infarcted myocardial tissue samples.
CONCLUSIONS
Our study for the first time demonstrated that RIPerc alleviates MIR-induced coronary artery endothelial dysfunction in non-occluded artery segments and attenuates aortic stiffness in rats. The vascular protective effects of RIPerc are associated with ameliorated inflammation and might therefore be caused by reduced inflammatory signaling.
Topics: Animals; Coronary Vessels; Cytokines; Inflammation; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Rats; Vascular Stiffness
PubMed: 34342526
DOI: 10.1177/10742484211031327 -
The American Journal of Chinese Medicine 2022Our study aimed to explore the function and mechanism of Dexmedetomidine (Dex) in regulating myocardial ischemia/reperfusion (I/R)-induced mitochondrial apoptosis...
Our study aimed to explore the function and mechanism of Dexmedetomidine (Dex) in regulating myocardial ischemia/reperfusion (I/R)-induced mitochondrial apoptosis through lncRNA HCP5. We demonstrated Dex suppressed I/R-induced myocardial infarction and mitochondrial apoptosis . Dex induced the expression of lncRNA HCP5 and MCL1, inhibited miR-29a expression and activated the JAK2/STAT3 signaling. Dex attenuated hypoxia/reoxygenation (H/R)-induced mitochondrial apoptosis by upregulating lncRNA HCP5 in cardiomyocytes. Overexpression of lncRNA HCP5 sponged miR-29a to suppress H/R-induced mitochondrial apoptosis. Knockdown of miR-29a also alleviated cardiomyocyte apoptosis by upregulating MCL1. Overexpression of lncRNA HCP5 activated the JAK2/STAT3 signaling through sponging miR-29a and enhancing MCL1 expression in cardiomyocytes. Dex mitigated myocardial I/R-induced mitochondrial apoptosis through the lncRNA HCP5/miR-29a/MCL1 axis and activation of the JAK2/STAT3 signaling.
Topics: Apoptosis; Dexmedetomidine; Humans; MicroRNAs; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; RNA, Long Noncoding
PubMed: 35931662
DOI: 10.1142/S0192415X22500641 -
Anastatin Derivatives Alleviate Myocardial Ischemia-Reperfusion Injury via Antioxidative Properties.Molecules (Basel, Switzerland) Aug 2021(±)-Anastatins A and B are flavonoids isolated from . In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their...
(±)-Anastatins A and B are flavonoids isolated from . In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their preliminary antioxidant activities were evaluated. In the present study, the protective effect of myocardial ischemia-reperfusion (I/R) and the systematic antioxidant capacity of 24 derivatives were further studied. Compound was the most potent among all the compounds studied, which increased the survival of H9c2 cells to 80.82%. The antioxidant capability of compound was evaluated in ferric reducing antioxidant power, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging, and 2,2-diphenyl-1-picrylhydrazyl assays. It was observed that compound significantly reduced infarcted areas and improved histopathological and electrocardiogram changes in rats with myocardial I/R injury. Moreover, compound decreased the leakage rates of serum lactate dehydrogenase, creatine kinase, and malonyldialdehyde from rat myocardial tissues and increased the level of glutathione and superoxide dismutase activities following myocardial I/R injury in rats. Taken together, we concluded that compound had potent cardioprotective effects against myocardial I/R injury both in vitro and in vivo owing to its extensive antioxidant activities.
Topics: Animals; Antioxidants; Apoptosis; Cell Survival; Flavonoids; Glutathione; Male; Malondialdehyde; Myocardial Reperfusion Injury; Oxidative Stress; Rats
PubMed: 34443365
DOI: 10.3390/molecules26164779 -
Molecular Medicine Reports Apr 2022Myocardial ischemia/reperfusion (MI/RI) syndrome is one of the leading causes of mortality and disability. Propofol postconditioning is known to improve myocardial...
Myocardial ischemia/reperfusion (MI/RI) syndrome is one of the leading causes of mortality and disability. Propofol postconditioning is known to improve myocardial ischemia/reperfusion injury (MI/RI). The present study aimed to explore the mechanism of propofol postconditioning in diabetic MI/RI. Diabetic MI/RI rat models were established and the rats were treated via propofol postconditioning. Staining with 2,3,5‑triphenyl‑2H‑tetrazolium chloride, H&E staining, TUNEL staining and ELISA were applied to detect infarct size, pathological changes, apoptosis and oxidative stress‑related factor and apoptotic factor levels, respectively. Subsequently, the effect of propofol on H9C2 cells was also assessed using the Cell Counting Kit‑8 assay. High‑glucose hypoxia/reperfusion (H/R) models of H9C2 cardiomyocytes were established. miR‑200c‑3p overexpression or AdipoR2 silencing combined with propofol postconditioning was performed in H/R‑induced H9C2 cells and STAT3 protein expression levels were determined. Propofol postconditioning significantly reduced myocardial infarct size, oxidative stress and apoptosis in diabetic MI/RI models. Furthermore, propofol postconditioning significantly reduced the oxidative stress and apoptosis of H9C2 cells in high‑glucose H/R models. Propofol postconditioning also significantly downregulated miR‑200c‑3p expression levels and promoted AdipoR2 expression levels. miR‑200c‑3p overexpression or AdipoR2 downregulation significantly reversed the effects of propofol postconditioning on its antioxidation and anti‑apoptotic effects in H9C2 cells and on decreasing STAT3 phosphorylation levels. Together, the results of the present study demonstrated that propofol postconditioning inhibited miR‑200c‑3p, upregulated AdipoR2 and activated the STAT3 signaling pathway, thus alleviating diabetic MI/RI and therefore highlighting its potential as a treatment of diabetic MI/RI.
Topics: Animals; Apoptosis; Diabetes Mellitus; MicroRNAs; Myocardial Reperfusion Injury; Myocytes, Cardiac; Propofol; Rats; Signal Transduction
PubMed: 35211763
DOI: 10.3892/mmr.2022.12653 -
Cardiovascular Research Mar 2020Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the...
AIMS
Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the 'right-level' of autophagy in the heart remains unidentified. Thioredoxin-interacting protein (TXNIP) is a pro-oxidative molecule knowing to contribute to I/R injury. However, whether and how TXNIP may further inhibit suppressed autophagy or promote excessive cardiac autophagy in I/R heart has not been previously investigated.
METHODS AND RESULTS
Wild type or gene-manipulated adult male mice were subjected to myocardial I/R. TXNIP was increased in myocardium during I/R. Cardiac-specific TXNIP overexpression increased cardiomyocytes apoptosis and cardiac dysfunction, whereas cardiac-specific TXNIP knock-out significantly mitigated I/R-induced apoptosis and improved cardiac function. Importantly, TXNIP overexpression significantly promoted cardiac autophagy and TXNIP knock-out significantly inhibited cardiac autophagy. In vitro studies demonstrated that TXNIP increased autophagosome formation but inhibited autophagosome clearance during myocardial reperfusion. Atg5 siRNA significantly decreased hypoxia/reoxygenation induced apoptosis in cardiomyocytes with TXNIP overexpression. Mechanistically, TXNIP suppressed autophagosome clearance via increasing reactive oxygen species (ROS) level. However, TXNIP-increased autophagosome formation was not mediated by ROS as a ROS scavenger failed to block increased autophagosome formation in TXNIP overexpression heart. Finally, TXNIP directly interacted and stabilized Redd1 (an autophagy regulator), resulting in mTOR inhibition and autophagy activation. Redd1 knock-down significantly reduced autophagy formation and ameliorated I/R injury in TXNIP overexpression hearts.
CONCLUSIONS
Our results demonstrated that increased TXNIP-Redd1 expression is a novel signalling pathway that contributes to I/R injury by exaggerating excessive autophagy during reperfusion. These observations advance our understanding of the mechanisms of myocardial I/R injury.
Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Carrier Proteins; Cells, Cultured; Disease Models, Animal; Hemodynamics; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases; Thioredoxins; Transcription Factors; Ventricular Function, Left
PubMed: 31241142
DOI: 10.1093/cvr/cvz152 -
Journal of Cardiovascular Pharmacology Jul 2021Long noncoding RNAs have been known to play key roles in myocardial ischemia/reperfusion injury. This study was conducted to investigate whether upregulation of FGD5-AS1...
Long noncoding RNAs have been known to play key roles in myocardial ischemia/reperfusion injury. This study was conducted to investigate whether upregulation of FGD5-AS1 can improve hypoxia/reoxygenation (H/R) injury of cardiomyocytes and its underlying mechanisms. Pc-FGD5-AS1 was used to overexpress FGD5-AS1 in cardiomyocytes. Cholecystokinin octapeptide and flow cytometry assays were performed to detect the effect of FGD5-AS1 on myocardial cell H/R injury. Quantitative real-time polymerase chain reaction and luciferase reporter assay were performed to assess the relationship between FGD5-AS1 and microRNA-106a-5p (miR-106a-5p) or miR-106b-5p. In patients with acute myocardial infarction and in H/R cardiomyocytes and ischemia/reperfusion myocardium, the expression levels of FGD5-AS1 were reduced, whereas the expression levels of miR-106a-5p and miR-106b-5p were increased. Overexpression of FGD5-AS1 increased the viability of H/R-treated cardiomyocytes and reduced the levels of apoptosis and creatine kinase-MB. In addition, FGD5-AS1 could bind to miR-106a-5p or miR-106b-5p and showed a mutual inhibitory effect between them. Furthermore, overexpression of miR-106a-5p or miR-106b-5p inhibited the expression of SMAD5. FGD5-AS1 upregulated the expression of SMAD5. In conclusion, FGD5-AS1 may be a potential therapeutic target for myocardial H/R injury, and its cardioprotective effect may be realized by reducing inflammatory response and cell apoptosis.
Topics: Animals; Apoptosis; Case-Control Studies; Cell Line; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Humans; MicroRNAs; Myocardial Reperfusion Injury; Myocytes, Cardiac; RNA, Long Noncoding; Rats; Smad5 Protein; Up-Regulation
PubMed: 34173804
DOI: 10.1097/FJC.0000000000001036 -
International Journal of Cardiology Oct 2019The improvement achieved in recent years in early myocardial infarction (MI) mortality poses several new clinical challenges, owing to late consequences of myocardial... (Review)
Review
The improvement achieved in recent years in early myocardial infarction (MI) mortality poses several new clinical challenges, owing to late consequences of myocardial loss and the significant incidence of heart failure (HF) observed thereafter. A still unaddressed residual reperfusion injury (RI) contributes to final infarct size, acute MI mortality and longer-term HF development. Despite many cardioprotective lines of research in the setting of MI, no treatment has significantly altered clinical practice or convincingly improved outcomes either. Left ventricular mechanical unloading before culprit vessel reopening may reduce RI and prime (biologically and mechanically) the myocardium for reperfusion, thus limiting infarct size and preventing subsequent adverse remodeling. Aim of this review is to summarize key pre-clinical and clinical experiences furnishing a rationale to the approach of mechanical unloading before myocardial reperfusion with a translational outlook on its implications for the management of MI patients.
Topics: Animals; Cardiac Output; Heart Failure; Humans; Myocardial Infarction; Myocardial Reperfusion; Ventricular Function, Left
PubMed: 31133434
DOI: 10.1016/j.ijcard.2019.05.042 -
Canadian Journal of Physiology and... Feb 2022Myocardial ischemia/reperfusion (I/R) injury causes irreversible injury to the heart, thereby causing acute myocardial infarction. Midazolam is a benzodiazepine commonly...
Myocardial ischemia/reperfusion (I/R) injury causes irreversible injury to the heart, thereby causing acute myocardial infarction. Midazolam is a benzodiazepine commonly utilized in anesthesia and intensive care. Research has indicated that midazolam plays a critical role in many diseases; however, the function of midazolam in myocardial injury induced by I/R still needs further investigation. The infarct size and damage to the heart tissues were examined through 2,3,5-triphenyl tetrazolium chloride (TTC) staining and hematoxylin and eosin staining. The creatine kinase-myocardial band isoenzyme, lactate dehydrogenase, and aspartate aminotransferase levels were tested using commercial kits. Cell apoptosis was determined through TUNEL staining or flow cytometry assays. Bax, Bcl-2, cleaved caspase-3, phospho-38 (p-p38), p38, p-JNK, JNK, extracellular signal-regulated kinases (ERK), and p-ERK expression was examined through Western blot. In our study, midazolam was shown to suppress the infarct size and heart tissue damage and reduce myocardial enzyme leakage in I/R rats. Additionally, midazolam was found to retard cardiomyocyte apoptosis in I/R rats. The JNK/p38 MAPK signaling pathway in I/R rats was inhibited by midazolam. Our findings demonstrated that in hypoxia/reoxygenation (H/R) - mediated H9C2 cells, anisomycin abolished the suppressive effects of midazolam on the JNK/p38 MAPK signaling pathway. Next, exploration discovered that anisomycin abolished the cytoprotective effects of midazolam on H/R-treated H9C2 cell apoptosis. In conclusion, this work demonstrated that midazolam retarded I/R-induced cardiomyocyte apoptosis by inhibiting the JNK/p38 MAPK signaling pathway. These results may provide new insight into the treatment of myocardial I/R injury.
Topics: Animals; Apoptosis; Cells, Cultured; Disease Models, Animal; JNK Mitogen-Activated Protein Kinases; Male; Midazolam; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats, Sprague-Dawley; Signal Transduction; p38 Mitogen-Activated Protein Kinases; Rats
PubMed: 34559975
DOI: 10.1139/cjpp-2021-0289 -
Journal of Cardiovascular Pharmacology... Nov 2020Translation of the cardioprotective effect by pharmacological and mechanical conditioning therapies into improvement of clinical outcome for the patients has been... (Review)
Review
Translation of the cardioprotective effect by pharmacological and mechanical conditioning therapies into improvement of clinical outcome for the patients has been disappointing. Confounding factors like comorbidity and comedications may explain some of the loss in translation. However, the substantial improvement of outcome in disease states involving ischemia-reperfusion injury, that is, planned cardiac surgery, elective percutaneous coronary intervention, and even primary percutaneous coronary intervention for ST-segment myocardial infarction (STEMI), is the most plausible explanation for the missed demonstration of a clinical benefit. Remote ischemic conditioning has demonstrated consistent cardioprotective effect in experimental and in clinical proof-of-concept studies. As an adjunctive cardioprotective treatment beyond reperfusion, remote ischemic conditioning should address target populations at risk of extensive tissue damage, including patients who experience complications, which may induce profound myocardial ischemia in relation to cardiac surgery or elective percutaneous coronary intervention. Moreover, patients with STEMI and predictable impaired clinical outcome due to delayed hospital admission, high Killip class, cardiogenic shock, and cardiac arrest remain target groups. For high-risk patients, daily remote ischemic conditioning or the corollary of blood flow-restricted exercise may be alternative cardioprotective options during postoperative and post-myocardial infarct rehabilitation.
Topics: Animals; Coronary Artery Bypass; Humans; Ischemic Postconditioning; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; Protective Factors; Risk Factors; Treatment Outcome
PubMed: 32597205
DOI: 10.1177/1074248420937871 -
Bioengineered Dec 2021Myocardial injury caused by ischemia-reperfusion is the main pathological manifestation of coronary artery disease (CAD), which is characterized by high mortality and...
Myocardial injury caused by ischemia-reperfusion is the main pathological manifestation of coronary artery disease (CAD), which is characterized by high mortality and morbidity. Thus, there's an urgent need to develop efficacious strategies and elucidate the underlying mechanisms to prevent or alleviate myocardial ischemia-reperfusion injury to improve the clinical outcomes in patients. In this study, we took advantage of a typical myocardial cell line of mice (HL-1) and cultured with or without an aquaporin 4 inhibitor (TGN-20 denoted as AQP4i) under normal conditions (NC), ischemia (IS) and ischemia reperfusion (IR), respectively. The cytomorphology, ultrastructure, cell vitality and expression pattern of apoptotic proteins were verified with scanning electron microscope (SEM), immunofluorescence staining, flow cytometry, quantitative real-time PCR and western-blotting analysis, respectively. HL-1 under IS or IR condition revealed higher expression of Aquaporin 4 (Aqp4) compared to the NC group, whereas showed similarity in cytomorphology and ultrastructure. Aqp4 inhibition was sufficient to improve the apoptotic cells in HL-1 while showed minimal effects to the other cellular vitality. Furthermore, the expression pattern of apoptotic proteins and anti-apoptotic proteins together with proinflammatory factors in HL-1 was effectively rescued by Aqp4i treatment both at the mRNA level and protein level. Ischemia and ischemia reperfusion caused higher expression of Aqp4 and resultant increase of cardiomyocyte pyroptosis. Myocardial ischemia-reperfusion injury of HL-1 was effectively alleviated by Aqp4 and pyroptosis inhibition. Our findings provided new references for myocardial ischemia-reperfusion injury management via targeting Aqp4-mediated pyroptosis of cardiomyocyte.
Topics: Animals; Aquaporin 4; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Pyroptosis
PubMed: 34657556
DOI: 10.1080/21655979.2021.1992332