Rosuvastatin exerts cardioprotective effect in lipopolysaccharide-mediated injury of cardiomyocytes in an MG53-dependent manner.

BACKGROUND: Myocarditis is a cardiomyopathy associated with the inflammatory response. Rosuvastatin (RS) demonstrates cardioprotective effect in the clinical setting, although its cellular and molecular mechanisms in ameliorating myocarditis are largely unknown. MG53 (muscle-specific E3 ligase Mitsugumin 53), a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. We aimed to explore whether RS mediated the repair of cardiomyocytes in an MG53-dependent manner. METHODS: The RS-induced upregulation of MG53 was determined using RT-qPCR and western blotting. A lipopolysaccharide (LPS)-induced cell inflammatory model was constructed using rat cardiac muscle cell H9C2. Inflammatory injury was evaluated according to the alterations of cell viability, mitochondrial membrane potential, cell apoptosis, and expression of pro-inflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1). Small interfering RNAs (siRNAs) were used to silence MG53. The cardioprotective effect of RS and the inhibition of this protection by MG53 silence were evaluated in the forementioned in vitro model. The underlying mechanism was finally investigated using western blotting to detected the expressions of apoptotic markers (Bcl-2, Bax, Cleaved caspase-9, Cleaved caspase-3), cell cycle regulatory factors (Cyclin A, Cyclin E1, Cyclin D1, CDK2), and components involved in NF-κB signaling pathway (p-IκBa, Iκba, p-p65, p65). RESULTS: RS ameliorated LPS-induced inflammatory injury. RS upregulated the expression of MG53. MG53 was crucial for the RS-mediated repair response in vitro. Ablation of MG53 inhibited the RS-mediated protective effect. Furthermore, RS and MG53 interact in multiple signaling pathways to modulate recovery. CONCLUSION: RS exerts cardioprotective effect in an MG53-dependent manner. MG53 may serve as a novel drug target for myocarditis treatment.

Certain aortic geometries and hemodynamics are associated with FID development and impact the evolution of uncomplicated type B intramural hematoma during the acute phase.

OBJECTIVES: It is difficult to predict the evolution of uncomplicated type B intramural hematoma (IMHB) with a focal intimal disruption (FID) in the acute phase. The aims of this study were to investigate the predictors of FIDs and summarize the risk factors for the evolution of uncomplicated IMHB in the acute phase. METHODS: Eighty-six patients with uncomplicated IMHB were included and were divided according to the development of an FID during the acute phase: the FID group (n = 32) and the no-FID group (n = 54). Geometric measurements and computed fluid dynamic calculations were based on a computed tomography scan performed on admission. Multivariate logistic regression analysis was used to estimate the predictors of FID development. RESULTS: Thirty-two (37%) patients developed an FID. Patients with an FID had higher C-reactive protein levels (18.6 ± 2.3 vs 8.1 ± 0.2 mg/dL, P < 0.001) and white blood cell counts (10.3 ± 2.1 vs 7.5 ± 1.7 109 /L, P < 0.001). The no-FID group had lower occurrences of disease progression (15% vs 64%, P < 0.001) and aorta-related mortality (6% vs 25%, P = 0.016). Multivariate logistic regression analysis indicated a significant risk for the occurrence of an FID with a larger maximum aortic diameter (OR, 1.35; 95% CI, 1.05-1.73, P = 0.020), thicker hematoma (OR, 2.20; 95% CI, 1.40-3.48, P = 0.001), and higher oscillatory shear index (per 0.01 unit, OR, 1.74; 95% CI, 1.21-2.49, P = 0.003). The aorta-related mortality during the acute phase was 25% (n = 8). CONCLUSIONS: Certain aortic conditions, including ta larger aortic diameter, thicker hematoma and higher oscillatory shear stress, are associated with the FID development and result in worse clinical outcomes.

A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice.

BACKGROUND STAT1/4 has been suggested to be involved in cardiac allograft rejection. However, no direct evidence regarding STAT3 has been established in cardiac allograft rejection. Here, we hypothesized that inhibition of STAT3 attenuates cardiac allograft rejection. MATERIAL AND METHODS To test our hypothesis, homotopic mouse heart transplantation was carried out in syngeneic C57BL/6 to C57BL/6 strain mice with or without oral gavage with NSC 74859, an inhibitor of STAT3. The immune response was investigated using real-time PCR for CD4 and CD8 surface makers of T cells and CD14 of monocytes and cytokines, including IL-2, IL-15, and IL-6 of allografts at 3, 6, and 9 days after transplantation. Prognosis was also evaluated. RESULTS We found that allografts with oral gavage of NSC 74859 whose CD4, CD8 T, and CD14 monocytes were significantly lower than that of allograft without oral gavage of NSC 74859, and the same was true for the expression of IL-2, IL-15, and IL-6. Immunohistochemical analysis of grafts showed reduced infiltration of monocytes/macrophages into the graft myocardium. Survival was also markedly extended in the NSC 74859 group. CONCLUSIONS Inhibition of IL-6/STAT3 using NSC 74859 was shown to remarkably alleviate cardiac allograft rejection in mice, indicating that the target against IL-6/STAT3 pathway might be clinically used as an alternative therapy for cardiac allograft rejection.

[Common factors for ischemic cerebral stroke in coronary artery bypass grafting in patients with concomitant carotid and coronary artery severe stenosis].

OBJECTIVE: To analyze two common factors for perioperative ischemic stroke in patients with concomitant carotid and coronary artery severe stenosis and to improve the therapeutic effect.
 Methods: A total of 44 patients with multi-vessel coronary artery disease combined with carotid stenosis, who admitted to the Department of Cardiac Surgery, the First Affiliated Hospital of Xiamen University from 2008 to 2014, were enrolled in this study. Among them, 32 cases were male, 12 cases was female. All patients received coronary artery bypass grafting after treatment of neck diseases. The surgical outcomes and follow-up results were analyzed retrospectively.
 Results: One patient received carotid endarterectomy suffered hemiplegia, whose symptoms were improved after positive clinical treatment. One patient suffered transient ischemic attack, and 5 patients displayed the cerebrovascular syndromes a week later after surgery. Twelve patients suffered nerve function damage 48 hours later after surgery. Nine patients received intra-aortic ballon pump, 1 patient received thoracotomy hemostasis, 3 patients suffered sternal dehiscence; 27 patients showed atrial fibrillation. Two patients died after surgery. The follow-up duration ranged from 1-7 years and the follow-up rate was 90%. The ischemic symptoms were improved in 44 patients. Six patients complained the recurrence of angina, but no abnormalities were found in coronary angiography or computed tomography angiography. One patient died of malignant tumor during the follow-up duration.
 Conclusion: For patients with concomitant carotid and coronary artery severe stenosis, it is more likely to suffer ischemic cerebral stroke. However, carotid stenosis is not the only factor, other key factors relevant to ischemic cerebral stroke shouldn't be ignored either.

Fullerene C60 Derivatives Attenuated Microglia-Mediated Prion Peptide Neurotoxicity.

Prion disorders are progressive neurodegenerative diseases characterized by extensive neuronal loss, which is linked to the extracellular accumulation of the scrapie isoform (PrPSC) of the normal cellular prion protein (PrPC). As microglial activation is a central event in pathogenesis of prion disease, the strategies that reduce microglial activation may have therapeutic benefits. In this study, the neuroprotective effects of hydroxylated C60(C60-OH) and amino modified-C60(C60-NH2) were evaluated by using PrP(106-126)-stimulated BV-2 cells as a model of activated microglia. Herein, we showed that microglial activation in response to PrP(106-126) was effectively attenuated by pretreatment with C60-OH as compared with C60-NH2. C60-OH significantly inhibited the excessive production of inflammatory mediators, such as prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factors (TNF)-α, interleukin (IL)-1ß, and IL-6, and blocked the expression of cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS) in PrP(106-126)-stimulated BV-2 cells. C60-OH exerted anti-inflammatory potential by up-regulating the expression of antioxidant enzymes via activation of nuclear factor erythroid 2-related factor 2 (Nrf2). The inhibitory effect of C60-OH against PrP(106-126)-induced inflammatory response was abolished by siRNA of Nrf2. In addition, conditioned culture media taken from PrP(106-126)-stimulated microglia cause apoptotic neuronal cell death, which was suppressed by pretreatment with C60-OH. Take together, these results suggest that C60-OH protects neuronal cells against PrP(106-126)-mediated neurotoxicity through activation of Nrf2 pathway, and provides evidence that fullerene derivatives may have therapeutic potential in prion diseases.