Nrf2 participates in the protective effect of exogenous mitochondria against mitochondrial dysfunction in myocardial ischaemic and hypoxic injury.

OBJECTIVE: Coronary artery disease is one of the leading causes of death worldwide. Treatments including coronary artery intervention can cause complications, such as myocardial ischaemia-reperfusion injury (MIRI). Mitochondrial injury or dysfunction is a key pathology of MIRI. Mitochondrial transplantation is considered a promising therapeutic strategy for cardiac-related diseases, but its mechanism is still unclear. Nrf2 is a prominent player in supporting the structural and functional integrity of mitochondria. In our research, we focused on the effect of Nrf2 in the treatment of MIRI by mitochondrial transplantation. H9C2 cells were subjected to hypoxia/reoxygenation (H/R) and MIRI was induced in wild-type and Nrf2-/- mice by surgical ligation of the left coronary artery to elucidate the mechanism in vitro and in vivo, respectively. Exogenous mitochondria were extracted from healthy H9C2 cells and the pectoralis major and administered to H9C2 cells and mice with MIRI, respectively. Mitochondrial internalization, H9C2 cell injury or apoptosis, cardiac injury/function, mitochondrial function, morphology, mitochondrial dynamics, and the expression of components of the Nrf2 pathway were assessed. We found that exogenous mitochondria were internalized into H9C2 cardiomyocytes. Exogenous mitochondrial transplantation attenuated cardiomyocyte injury, cardiomyocyte apoptosis, and mitochondrial dysfunction. Exogenous mitochondrial transplantation increased the expression of Nrf2 and its downstream targets, attenuated cardiomyocyte injury, cardiac dysfunction, apoptosis, mitochondrial dysfunction, and mitochondrial fusion and fission imbalance, and improved mitophagy after MIRI in wild-type mice but not in Nrf2-/- mice. These results suggested that exogenous mitochondria can be internalized into cardiomyocytes and activate the Nrf2 pathway and that exogenous mitochondria improve cardiac function and ameliorate mitochondrial dysfunction via the Nrf2 pathway.

Effect of dexmedetomidine on hemodynamic changes and inflammatory responses in patients undergoing off-pump coronary-artery bypass grafting.

The aim of the present study was to determine the effect of dexmedetomidine on hemodynamic changes and inflammatory responses in patients undergoing off-pump coronary artery bypass grafting (OPCABG). A total of 300 patients about to receive OPCABG were randomized evenly into the control group (n=116) and study group (n=123). Intravenous dexmedetomidine pump infusion was administered to patients in the study group at a rate of 0.4 µg.kg-1.h-1. The control group received physiological saline at the same infusion speed. Changes in hemodynamic parameters and inflammatory indices were compared between the two groups. Hemodynamic parameters, such as the heart rate and mean arterial pressure, were lower in patients from the study group, compared with that in the control group (both P<0.05). The levels of pro-inflammatory factors, such as interleukin (IL)-6, tumor necrosis factor-α and C-reactive protein, were also reduced in the study group (P<0.05). The observed levels of IL-10 were lower in the control group compared with that in the study group, although a statistically significant difference was not achieved. Thus, the administration of dexmedetomidine in patients undergoing OPCABG stabilized hemodynamics and reduced inflammation. The present study was registered at the Chinese Clinical Trial Registry, under the trial registration number ChiCTR-OOC-15005978 (2015).

MicroRNA-34c Inhibits Osteogenic Differentiation and Valvular Interstitial Cell Calcification via STC1-Mediated JNK Pathway in Calcific Aortic Valve Disease.

Calcific aortic valve disease (CAVD), a common heart valve disease, is increasingly prevalent worldwide and causes high morbidity and mortality. Here, we aimed to investigate a possible role for miR-34c in the development of osteogenic differentiation during CAVD and to find out the underlying mechanisms. Valvular interstitial cells (VICs) were isolated from the clinical aortic valve tissue samples of CAVD patients and patients with acute aortic dissection and collected. Then, RT-qPCR was performed to determine miR-34c expression and western blot analysis was applied to confirm the relevant protein expression in these VICs. Dual luciferase reporter gene assay was applied to confirm the relation between miR-34c and STC1. Alkaline phosphatase (ALP) staining and alizarin red staining was performed to further confirm the degree of calcification in these samples. MiR-34c was lowly expressed and STC1 was highly expressed in the CAVD tissues. Furthermore, STC1 was the target of miR-34c and was negatively regulated by miR-34c. Overexpression of miR-34c in VICs was concomitant with suppression of both STC1 expression and phosphorylation level of c-Jun N-terminal kinase (JNK). In addition, significant decrease of bone morphogenetic protein-2 (BMP2) and osteocalcin, as well as the decrease of calcification degree were also observed in VICs with miR-34c overexpressed. Taken together, miR-34c could inhibit osteogenic differentiation and calcification of VICs by suppressing the STC1/JNK signaling pathway in CAVD, making miR-34c a novel therapeutic target for the treatment of CAVD.

Upregulation of microRNA-195 ameliorates calcific aortic valve disease by inhibiting VWF via suppression of the p38-MAPK signaling pathway.

BACKGROUND: Growing evidence has indicated that microRNAs (miRNAs) are involved in the progression of calcific aortic valve disease (CAVD), a progressive pathological condition with no effective pharmacological therapy. This study was set out with the aim to investigate possible roles of miR-195 in CAVD. METHODS AND RESULTS: Initially, the differential expressed genes (DEGs) associated with CAVD were screened out and miRNAs potentially regulating VWF were predicted from microarray analysis. Next, we quantified VWF and miR-195 expression in isolated aortic valve interstitial cells (AVICs) and aortic valve tissues, followed by confirmation of the target relationship between miR-195 and VWF using the dual luciferase reporter assay. Furthermore, we evaluated the biological functions of miR-195 and VWF on ALP activity, cell differentiation, and the levels of miR-195, VWF, Runx2, OCN, ALP, p38 and phosphorylated p38 in AVICs. VWF was highly expressed, while miR-195 was poorly expressed in CAVD. Furthermore, miR-195 targeted VWF and negatively regulated its expression. Upregulation of miR-195 or silencing VWF could reduce ALP activity, calcified deposition, and the mRNA and protein levels of Runx2, OCN, and ALP by inhibiting the p38-MAPK signaling pathway, thereby ameliorating aortic valve calcification in vitro. CONCLUSIONS: On all accounts, miR-195 can potentially inhibit aortic valve calcification by repressing VWF and p38-MAPK signaling pathway, highlighting a theoretical basis for pharmacological treatment of CAVD.

18 Fluorodeoxyglucose-positron emission tomography/computed tomography features of suspected solitary pulmonary lesions in breast cancer patients following previous curative treatment.

BACKGROUND: Differentiating pulmonary metastasis from primary lung cancer can be challenging in patients with breast malignancy. This study aimed to characterize the imaging features of 18 fluorodeoxyglucose-positron emission tomography/computed tomography (18 F-FDG-PET/CT) for distinguishing between these diseases. METHODS: We enrolled 52 patients who received curative treatment for breast cancer but later presented with suspected solitary pulmonary lesions (SPLs) and subsequently underwent 18 F-FDG-PET/CT to investigate. RESULTS: Subsolid lesions, ill-defined borders, lung lesions with negative maximum standardized uptake value, and lesions without 18 F-FDG-PET/CT-diagnosed hilar and/or mediastinal lymph nodes and pleural metastases were more likely to be associated with primary lung cancer. CONCLUSIONS: CT border, FDG uptake, hilar and/or mediastinal lymph node metastasis, and pleural metastasis are potential markers for diagnosis.