Coronary microembolization (CME), a common reason for periprocedural myocardial infarction (PMI), bears very important prognostic implications. However, the molecular mechanisms related to CME remain largely elusive. Statins have been shown to prevent PMI, but the underlying mechanism has not been identified. Here, we examine whether the NLRP3 inflammasome contributes to CME-induced cardiac injury and investigate the effects of statin therapy on CME. In vivo study, mice with CME were treated with 40 mg/kg/d rosuvastatin (RVS) orally or a selective NLRP3 inflammasome inhibitor MCC950 intraperitoneally (20 mg/kg/d). Mice treated with MCC950 and RVS showed improved cardiac contractile function and morphological changes, diminished fibrosis and microinfarct size, and reduced serum lactate dehydrogenase (LDH) level. Mechanistically, RVS decreased the expression of NLRP3, caspase-1, interleukin-1β, and Gasdermin D N-terminal domains. Proteomics analysis revealed that RVS restored the energy metabolism and oxidative phosphorylation in CME. Furthermore, reduced reactive oxygen species (ROS) level and alleviated mitochondrial damage were observed in RVS-treated mice. In vitro study, RVS inhibited the activation of NLRP3 inflammasome induced by tumor necrosis factor α plus hypoxia in H9c2 cells. Meanwhile, the pyroptosis was also suppressed by RVS, indicated by the increased cell viability, decreased LDH and propidium iodide uptake in H9c2 cells. RVS also reduced the level of mitochondrial ROS generation in vitro. Our results indicate the NLRP3 inflammasome-dependent cardiac pyroptosis plays an important role in CME-induced cardiac injury and its inhibitor exerts cardioprotective effect following CME. We also uncover the anti-pyroptosis role of RVS in CME, which is associated with regulating mitochondrial ROS.
PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRK-AG2 gene that encodes γ2 regulatory subunit of AMP-activated protein kinase. Affected patients usually develop ventricular tachyarrhythmia and experience progressive heart failure that is refractory to medical treatment and requires cardiac transplantation. In this study, we identify a H530R mutation in PRKAG2 from patients with familial Wolff-Parkinson-White syndrome. By generating H530R PRKAG2 transgenic and knock-in mice, we show that both models recapitulate human symptoms including cardiac hypertrophy and glycogen storage, confirming that the H530R mutation is causally related to PRKAG2 cardiac syndrome. We further combine adeno-associated virus-9 (AAV9) and the CRISPR/Cas9 gene-editing system to disrupt the mutant PRKAG2 allele encoding H530R while leaving the wild-type allele intact. A single systemic injection of AAV9-Cas9/sgRNA at postnatal day 4 or day 42 substantially restores the morphology and function of the heart in H530R PRKAG2 transgenic and knock-in mice. Together, our work suggests that in vivo CRISPR/Cas9 genome editing is an effective tool in the treatment of PRKAG2 cardiac syndrome and other dominant inherited cardiac diseases by selectively disrupting disease-causing mutations.
Purpose
Quadratus lumborum block (QLB) is shown to be effective on analgesia following cesarean section. This study aimed to compare the effects of three practical QLB approaches and classic epidural analgesia (EA) for cesarean section under spinal anesthesia.
Patients and methods
Parturients undergoing elective cesarean section were randomized as group 1 (QLB type 2), group 2 (QLB type 3), group 3 (QLB type 2+3) and group 4 (EA). The block was performed at the end of the operation, and the epidural group was given a single epidural bolus. All subjects were provided with intravenous patient-controlled analgesia under identical settings. In addition, the postoperative pain severity was assessed by the VAS, which together with the morphine consumption at specific time intervals, was recorded within 48 hrs after surgery. Data were collected from December 2017 to June 2018.
Results
A total of 94 parturients had completed the study. At almost all postoperative time points, the VAS scores at rest and with movement in QLB type 2+3 group were lower than those in QLB type 2 or 3 group. The mean additional morphine consumption in QLB type 2+3 group (2.7 mg) was lower than that in QLB type 2 or 3 group (6.1 mg and 5.7 mg, respectively) within 48 h after surgery (
P
<0.001). Besides, the total morphine consumption in EA group (1.3 mg) was lower than that in any other QLB group (
P
<0.001).
Conclusions
The analgesic effect of QLB is highly dependent on the injection position of local anesthetic. Besides, the ultrasound-guided QLB type 2+3 can provide superior analgesic effect following cesarean section to that of QLB type 2 or 3 block. However, it remains to be further validated about whether the combination of QLB type 2 and 3 is the best approach.
Current evidence indicates that coronary microcirculation is a key target for protecting against cardiac ischemia–reperfusion (I/R) injury. Mitochondrial calcium uniporter (MCU) complex activation and mitochondrial calcium ([Ca2+]m) overload are underlying mechanisms involved in cardiovascular disease. Histidine triad nucleotide-binding 2 (HINT2) has been reported to modulate [Ca2+]m via the MCU complex, and our previous work demonstrated that HINT2 improved cardiomyocyte survival and preserved heart function in mice with cardiac ischemia. This study aimed to explore the benefits of HINT2 on cardiac microcirculation in I/R injury with a focus on mitochondria, the MCU complex, and [Ca2+]m overload in endothelial cells. The present work demonstrated that HINT2 overexpression significantly reduced the no-reflow area and improved microvascular perfusion in I/R-injured mouse hearts, potentially by promoting endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Microvascular barrier function was compromised by reperfusion injury, but was repaired by HINT2 overexpression via inhibiting VE-Cadherin phosphorylation at Tyr731 and enhancing the VE-Cadherin/β-Catenin interaction. In addition, HINT2 overexpression inhibited the inflammatory response by suppressing vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mitochondrial fission occurred in cardiac microvascular endothelial cells (CMECs) subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) injury and resulted in mitochondrial dysfunction and mitochondrion-dependent apoptosis, the effects of which were largely relieved by HINT2 overexpression. Additional experiments confirmed that [Ca2+]m overload was an initiating factor for mitochondrial fission and that HINT2 suppressed [Ca2+]m overload via modulation of the MCU complex through directly interacting with MCU in CMECs. Regaining [Ca2+]m overload by spermine, an MCU agonist, abolished all the protective effects of HINT2 on OGD/R-injured CMECs and I/R-injured cardiac microcirculation. In conclusion, the present report demonstrated that HINT2 overexpression inhibited MCU complex-mitochondrial calcium overload-mitochondrial fission and apoptosis pathway, and thereby attenuated cardiac microvascular ischemia–reperfusion injury.
BackgroundFemoral nerve block (FNB) has been considered as an excellent analgesic modality in total knee arthroplasty (TKA) pain control. However, relatively high concentration of ropivacaine could lead to quadriceps muscle weakness and increase the risk of postoperative falls.ObjectiveThis double-blinded randomized controlled study was designed to investigate the effect of a combination of dexmedetomidine with a lower concentration of ropivacaine on quadriceps muscle strength and analgesic effect in FNB.MethodsA total of 90 patients scheduled for TKA were randomized to receive continuous FNB postoperatively using 0.2% ropivacaine (H group), 0.1% ropivacaine (L group) or 0.1% ropivacaine combined with 2 μg/kg dexmedetomidine (LD group). Meanwhile, intravenous patient-controlled analgesia with morphine was administered to patients. The primary endpoint was the strength of quadriceps muscle evaluated by manual muscle testing (MMT) and Timed Up and Go test (TUG). The secondary endpoint was the pain scores and morphine consumption among different groups.ResultsFor MMT, LD group showed higher quadriceps muscle strength than the other two groups (P<0.05) at 12 hrs postoperatively. TUG test was conducted to measure the walking ability, and showed that scores were significantly better in LD group than those in H group and L group (P<0.05) at 24 and 48 hrs postoperatively. There was no significant difference between H and LD group in the numeric rating scales (NRS) scores both at rest and at 45° flexion. The total morphine consumption in L group was significantly higher than in H or LD group (P<0.001).ConclusionCollectively, the addition of dexmedetomidine 2 μg/kg to 0.1% ropivacaine preoperatively would preserve quadriceps muscle strength with satisfactory analgesia in patients undergoing TKA. (This study was registered at ClinicalTrials.gov, identifier NCT03658421).
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