Yunzeng Zou

The immune inflammatory response plays a crucial role in many cardiac pathophysiological processes, including ischaemic cardiac injury and the post‐infarction repair process. MicroRNAs (miRNAs) regulate the development and function of dendritic cells (DCs), which are key players in the initiation and regulation of immune responses; however, the underlying regulatory mechanisms remain unclear. Here, we used the supernatants of necrotic primary cardiomyocytes (Necrotic‐S) to mimic the myocardial infarction (MI) microenvironment to investigate the role of miRNAs in the regulation of DC‐mediated inflammatory responses. Our results showed that Necrotic‐S up‐regulated the DC maturation markers CD40, CD83 and CD86 and increased the production of inflammatory cytokines, concomitant with the up‐regulation of miR‐181a and down‐regulation of miR‐150. Necrotic‐S stimulation activated the JAK/STAT pathway and promoted the nuclear translocation of c‐Fos and NF‐κB p65, and silencing of STAT1 or c‐Fos suppressed Necrotic‐S‐induced DC maturation and inflammatory cytokine production. The effects of Necrotic‐S on DC maturation and inflammatory responses, its activation of the JAK/STAT pathway and the induction of cardiomyocyte apoptosis under conditions of hypoxia were suppressed by miR‐181a or miR‐150 overexpression. Taken together, these data indicate that miR‐181a and miR‐150 attenuate DC immune inflammatory responses via JAK1–STAT1/c‐Fos signalling and protect cardiomyocytes from cell death under conditions of hypoxia.

Background: In this study, we tested the hypothesis that miR-181a levels increase during acute myocardial infarction. We investigated circulating miR-181a as a potential novel biomarker for early diagnosis of acute myocardial infarction (AMI). Methods: From June 2014 to June 2016, 120 consecutive eligible patients with AMI (n = 60) or unstable angina (UA; n = 60) and 60 control subjects were enrolled. Plasma miR-181a levels were determined by quantitative reverse transcriptase-polymerase chain reaction. Results: Circulating miR-181a expression levels detected immediately after admission were higher in the AMI group than in the UA and control groups. Relative miR-181a levels in AMI patients were positively correlated with the concentrations of the creatine kinase-MB fraction and cardiac troponin I. Correlation analysis showed that plasma miR-181a was positively correlated with coronary Gensini score (r = 0.573, P < 0.05) and negatively correlated with left ventricular ejection fraction (r = -0.489, P < 0.05). Receiver operating characteristic curve analyses showed that plasma miR-181a was of significant diagnostic value for AMI (AUC, 0.834; 95% CI, 0.756-0.912, P < 0.05). Conclusion: Circulating miR-181a levels in patients with AMI were significantly changed in a time-dependent manner, indicating the value of plasma miR-181a as a novel biomarker for diagnosing AMI.

Background: Here, we determined miR-499 involvement in the protective effect of ischemic postconditioning (IPC) against myocardial ischemia/reperfusion (I/R) injury and identified the underlying mechanisms. Methods: To investigate the cardioprotective effect of IPC-induced miR-499, rats were divided into the following five groups: sham, I/R, IPC, IPC + scramble, and IPC + antagomiR-499. Hemodynamic indexes were measured by carotid-artery intubation to assess left ventricular function . Ischemia and infarction areas of rat hearts were determined by Evans blue and triphenyltetrazolium chloride staining, and cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end-labeling assay. Results: IPC attenuated I/R-induced infarct size of the left ventricle (45.28 ± 5.40% vs. 23.56 ± 6.20%, P < 0.05), myocardial apoptosis, and decreased creatine kinase (1867.31 ± 242.41% vs. 990.21 ± 172.39%, P < 0.05), lactate dehydrogenase (2257.50 ± 305.11% vs. 1289.11 ± 347.28%, P < 0.05), and malondialdehyde levels (7.18 ± 1.63% vs. 4.85 ± 1.52%, P < 0.05). Additionally, left ventricular systolic pressure, +dp/dtmax, and -dp/dtmax were elevated, and left ventricular end diastolic pressure was significantly reduced in the IPC group. Furthermore, IPC-mediated cardiac protection against I/R injury was inhibited in vivo and in vitro by knockdown of cardiac miR-499, suggesting that miR-499 may participate in the protective function of IPC against I/R injury through targeting programmed cell death 4 (PDCD4). Conclusion: Our data revealed that IPC-regulated miR-499 plays an important role in IPC-mediated cardiac protection against I/R injury by targeting PDCD4.

Objectives The effect of high density lipoprotein (HDL) on the secretome of mesenchymal stem cells (MSCs) has not been well elucidated yet. The aim of the study is to examine the hypothesis that preconditioning with HDL promotes MSCs secretome, subsequently protecting cardiomyocytes from hypoxia. Methods MSCs derived from bone marrow of rats were preconditioned with HDL in various concentrations or for different periods. Afterwards, the mRNA of some soluble factors (including VEGF, bFGF, HGF, TGF-β2) in MSCs was analysed by real-time PCR, and the levels of above factors in supernatant were analysed by ELISA. Cardiomyocytes of neonatal rats were exposed to hypoxia for 12 h, incubated in culture medium which were respectively added with the supernatant filtered from MSCs and HDL cultured system (MSCs+HDL), from MSCs alone cultured medium (MSCs), or the same terminal concentration of HDL (HDL) or PBS (Control). Apoptosis of cardiomyocytes was evaluated by TUNEL assay and western-blot. RNA interference was administrated to confirm the effect of soluble factors on the cardiomyocytes (siRNA) apoptosis, in which flow cytometry was addressed to evaluate the apoptosis rate. Results When MSCs were exposed to HDL, the expression of TGF-β2, both mRNA level in MSCs and protein level in supernatant, increased significantly in a time- and concentration-dependent manner. Group(MSCs+HDL) exhibited remarkable lower apoptosis rate compared with Group(Control), Group(HDL), Group(MSCs) (TUNEL: (10.23±5.68)% vs (28.36±4.98)%, vs (16.38±5.38)%, vs (17.82±6.24)%, p value allConclusions TGF-β2 released by mesenchymal stem cells preconditioned with high density lipoprotein protects cardiomyocytes from injury of hypoxia.

Aims To examine whether adiponectin is associated with disease progression of heart failure from hypertension in rats in comparison with other known biomarkers and echocardiographic parameters. Methods Spontaneously hypertensive rats (SHR, n=35), aged 1 month, were used and followed up to 18 months. High frequency echocardiography was performed both at baseline and every 3 months thereafter. Moreover, serum levels of N-terminal pro-natriuretic peptide (NT-proBNP) and interleukin 6 (IL-6) as well as serum level and tissue expression of adiponectin were measured in the same time as echocardiography. Results Our results clearly demonstrated time-dependent progression of hypertension and heart dysfunction as evidenced by gradually increased left ventricular mass index, NT-proBNP, IL-6 and gradually decreased cardiac function as assessed by echocardiography. Meanwhile, tissue and serum adiponectin decreased from 3 months and reached plateau until 12 month in parallel with decreasing of cardiac diastolic function and then kept increasing prior to occurrence of systolic dysfunction. And adiponectin concentration is inversely related with NT-proBNP, IL-6 and E/E′ (correlation coefficient (r)=−0.756 for NT-proBNP, pConclusions Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction.