Uncoupling protein 2 (UCP2), located in the mitochondrial inner membrane, is a predominant isoform of UCP that expressed in the heart and other tissues of human and rodent tissues. Nevertheless, its ...functional role during myocardial ischemia/reperfusion (I/R) is not entirely understood. Ischemic preconditioning (IPC) remarkably improved postischemic functional recovery followed by reduced lactate dehydrogenase (LDH) release with simultaneous upregulation of UCP2 in perfused myocardium. We then investigated the role of UCP2 in IPC‐afforded cardioprotective effects on myocardial I/R injury with adenovirus‐mediated in vivo UCP2 overexpression (AdUCP2) and knockdown (AdshUCP2). IPC‐induced protective effects were mimicked by UCP2 overexpression, while which were abolished with silencing UCP2. Mechanistically, UCP2 overexpression significantly reinforced I/R‐induced mitochondrial autophagy (mitophagy), as measured by biochemical hallmarks of mitochondrial autophagy. Moreover, primary cardiomyocytes infected with AdUCP2 increased simulated ischemia/reperfusion (sI/R)‐induced mitophagy and therefore reversed impaired mitochondrial function. Finally, suppression of mitophagy with mdivi‐1 in cultured cardiomyocytes abolished UCP2‐afforded protective effect on sI/R‐induced mitochondrial dysfunction and cell death. Our data identify a critical role for UCP2 against myocardial I/R injury through preventing the mitochondrial dysfunction through reinforcing mitophagy. Our findings reveal novel mechanisms of UCP2 in the cardioprotective effects during myocardial I/R.
Our data identify a critical role for uncoupling protein 2 (UCP2) against myocardial ischemia/reperfusion (I/R) injury through preventing the mitochondrial dysfunction through reinforcing mitophagy. Our findings reveal novel mechanisms of UCP2 in the cardioprotective effects during myocardial I/R.
miRNA‐mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R ...condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR‐383‐dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR‐383 overexpression or miR‐383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR‐383. Pyroptosis‐related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis‐related mediators including NLRP3, cleaved caspase‐1, cleaved IL‐1β and IL‐18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI‐caused elevation of miR‐383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR‐383 target. miR‐383 knockdown ameliorated but miR‐383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti‐pyroptotic effect from miR‐383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR‐383/RP105/AKT‐dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR‐383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.
Apoptosis is the major cause of cardiomyocyte death in myocardial ischemia/reperfusion injury (MI/RI). Increasing evidence suggests that microRNAs (miRNAs) can contribute to the regulation of ...cardiomyocytes apoptosis by posttranscriptional modulation of gene expression networks. However, the effects of miR‐327 in regulating MI/RI‐induced cardiomyocytes apoptosis have not been extensively investigated. This study was performed to test whether miR‐327 participate in cardiomyocytes apoptosis both in vitro and in vivo, and reveal the potential molecular mechanism of miR‐327 regulated MI/RI through targeting apoptosis repressor with caspase recruitment domain (ARC). Sprague–Dawley (SD) rats were subjected to MI/RI by left anterior descending coronary artery occlusion for 30 min and reperfusion for 3 hr. H9c2 cells were exposed to hypoxia for 4 hr and reoxygenation for 12 hr to mimic I/R injury. miRNA‐327 recombinant adenovirus vectors were transfected into H9c2 cells for 48 hr and rats for 72 hr before H/R and MI/RI treatment, respectively. The apoptosis rate, downstream molecules of apoptotic pathway, and the target reaction between miRNA‐327 and ARC were evaluated. Our results showed that miR‐327 was upregulated and ARC was downregulated in the myocardial tissues of MI/RI rats and in H9c2 cells with H/R treatment. Inhibition of miR‐327 decreased the expression levels of proapoptotic proteins Fas, FasL, caspase‐8, Bax, cleaved caspase‐9, cleaved caspase‐3, and the release of cytochrome‐C, as well as increasing the expression levels of antiapoptotic protein Bcl‐2 via negative regulation of ARC both in vivo or vitro. In contrast, overexpression miR‐327 showed the reverse effect. Moreover, the results of luciferase reporter assay indicated miR‐327 targets ARC directly at the posttranscriptional level. Taken together, inhibition of miR‐327 could attenuate cardiomyocyte apoptosis and alleviate I/R‐induced myocardial injury via targeting ARC, which offers a new therapeutic strategy for MI/RI.
In summary, inhibition of miR‐327 may alleviate I/R‐induced myocardial injury and suppress both extrinsic and intrinsic apoptotic cascades after myocardial ischemia/reperfusion injury (MI/RI) by targeting ARC. The manipulation of miR‐327‐mediated ARC stability may offer a new therapeutic strategy for MI/RI.
Myocardial ischemia and reperfusion (I/R) injury is a pathological condition characterized by an initial restriction of blood supply to the heart followed by the subsequent restoration of perfusion ...and concomitant re-oxygenation. This condition may cause heart injury and contribute to morbidity and mortality. Although tremendous advances have been made in understanding the mechanisms of myocardial I/R injury, the translation of these findings into the clinical setting has been largely disappointing. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs ranging from 18-24 nucleotides in length. They are highly conserved and ubiquitously expressed in all species, which control diverse cellular functions by either promoting degradation or inhibiting target mRNA translation. In particular, a multitude of studies demonstrated miRNAs played an important role in acute and chronic cardiovascular disease processes. In this review, we focus on miRNAs and summarize the latest insights on the role of the specific miRNAs in myocardial I/R injury.
Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R). Toll-like receptor 4 (TLR4) is a potent inducer of these apoptotic cascades. In ...contrast, the radioprotective 105 kDa protein (RP105) is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI). Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham). After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.
Fluvastatin, a traditional fat-decreasing drug, is widely used for curing cardiovascular disease. Previous reports demonstrated that fluvastatin pretreatment protected against myocardial ...ischemia/reperfusion (I/R) by inhibiting TLR4 signaling pathway and/or reducing proinflammatory cytokines. However, whether fluvastatin has a cardioprotective effect against apoptosis and autophagy remains unknown. This study aims to evaluate whether the cardioprotective role of fluvastatin in I/R is mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) pathway via anti-apoptotic and anti-autophagic functions. Sprague–Dawley rats were anesthetized, artificially ventilated and subjected to 30 min of coronary occlusion, followed by 4 h of reperfusion. The animals were randomized into four groups: (i) Sham operation; (ii) I/R; (iii) I/R + low-dosage fluvastatin (10 mg/kg); and (iv) I/R + high-dosage fluvastatin (20 mg/kg). After reperfusion, the hemodynamic parameters, myocardial infarct size, structural alteration of myocardium, apoptosis index, pro-inflammatory cytokine production, Beclin-1, Light chain 3 (LC3), HMGB1, TLR4 and Nuclear factor kappa B (NF-κB) protein levels were measured and recorded. It was found that fluvastatin preconditioning improved left ventricular dysfunction, reduced HMGB1/TLR4/NF-κB expressions, and inhibited cardiomyocyte apoptosis, autophagy, and inflammation reaction. Moreover, treatment with fluvastatin ameliorated myocardial injury by reducing infarct size, causing less damage to cardiac structure, downregulating autophagy-related protein expression and releasing pro-inflammation mediators. Our findings indicate that fluvastatin exerts beneficial effects on cardiac ischemic damage, which may be associated with its anti-autophagic and anti-apoptotic functions via inhibition of HMGB1/TLR4-related pathway during I/R injury.
: The optimal duration of dual antiplatelet therapy (DAPT) in patients after PCI with implantation of a drugeluting stent is still controversial. We conducted a meta-analysis to compare the efficacy ...and safety of short term DAPT (≤ 3 months) followed by P2Y12 inhibitor monotherapy and standard DAPT (12 months) after PCI.
: Relevant studies published in Medline, Embase, CoChrane Library were searched for randomized controlled trials (RCTs) until November 2019. Studies were screened by selection criteria then quality assessed through the Cochrane Collaboration's tool. Data were extracted from the included studies and statistically analyzed by RevMan 5.3 software.
: Five RCTs (n=18,357) were included. Compared with standard DAPT, the short term DAPT was associated with a significant decrease in the major bleeding odds ratio (OR)=0.43, 95% Confidence Interval (CI):0.32-0.58,
<0.00001 and any bleeding OR=0.56, 95%CI:0.47-0.66, P<0.00001. There were no significant differences in all-cause death OR=0.91, 95%CI:0.71-1.16,
=0.45, major adverse cardiac and cerebrovascular event OR=1.01, 95%CI:0.87-1.17,
=0.91 and stent thrombosis OR=0.97, 95%CI:0.61-1.54,
=0.91 between with the short term DAPT group and the standard DAPT group.
Short term DAPT followed by P2Y12 monotherapy could reduce the risk of bleeding without increasing the incidence of ischemic events after PCI with implantation of second-generation DES compared with standard DAPT. Therefore, short term DAPT may be a promising strategy to balance ischemic events and bleeding complications in patients after PCI.
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