Role of PI3K/AKT/mTOR Pathway Associated Oxidative Stress and Cardiac Dysfunction in Takotsubo Syndrome.

INTRODUCTION: Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy, but the accurate cause of this syndrome is still unknown. METHODS: ß-adrenergic agonist isoproterenol (ISO) is used to establish the TTS rats model. TTS rats were treated with or without LY294002 or Rapamycin. The rat cardiomyoblast cell line H9C2 was subjected to infect with constitutively active Akt (myr-Akt) or dominant-negative mutant Akt (dn-Akt) and then, treated with ISO. Cell apoptosis was assessed using the Bax/ Bcl-2 ratio. In addition, reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE). Mitochondrial superoxide generation and membrane potential were assayed by MitoSOX and JC-1 fluorescence intensity. RESULTS: ISO might induce the erratic acute cardiac dysfunction and overexpression of PI3K/AKT/mTOR. Moreover, it also increased the oxidative stress and apoptosis in TTS rats. The Akt inhibitor significantly reversed the cardiac injury effect, which triggered by ISO treatment. In H9C2 cells, the inhibition of Akt provides a protective role against ISO-induced injury by reducing oxidative stress, apoptosis and mitochondrial dysfunction. CONCLUSION: This study provided new insight into the protective effects of myocardial dysfunction in TTS rats via chronic inhibition of the PI3K/AKT/mTOR expression, which could reduce mitochondrial ROS and oxidative stress-induced apoptosis. PI3K/AKT/mTOR inhibitor could be a therapeutic target to treat cardiovascular dysfunction induced by stress cardiomyopathy.

Electrocardiogram patterns during hemodynamic instability in patients with acute pulmonary embolism.

BACKGROUND: We have previously described new electrocardiogram (ECG) findings for massive pulmonary embolism, namely ST-segment elevation in lead aVR with ST-segment depression in leads I and V4 -V6 . However, the ECG patterns of patients with acute pulmonary embolism during hemodynamic instability are not fully described. METHODS: We compared the differences between the ECG at baseline and after deterioration during hemodynamic instability in twenty patients with acute pulmonary embolism. RESULTS: Compared with the ECG at baseline, three ischemic ECG patterns were found during clinical deterioration with hemodynamic instability: ST-segment elevation in lead aVR with concomitant ST-segment depression in leads I and V4 -V6 , ST-segment elevation in leads V1 -V3 /V4 , and ST-segment elevation in leads III and/or V1 /V2 with concomitant ST-segment depression in leads V4 /V5 -V6 . Ischemic ECG patterns with concomitant S1Q3 and/or abnormal QRS morphology in lead V1 were more common (90%) during hemodynamic instability than at baseline (5%) (P = 0.001). CONCLUSIONS: Hemodynamic instability in acute pulmonary embolism is reflected by signs of myocardial ischemia combined with the right ventricular strain pattern in the 12-lead ECG.

Effect of hyperlipidemia on Foxp3 expression in apolipoprotein E-knockout mice.

BACKGROUND: The transcription factor forkhead box P3 (Foxp3) plays an essential role in the development and function of regulatory T cells. AIMS: To examine the effect of hyperlipidemia on the expression of Foxp3 in mice. METHODS: Twenty-four 8-week-old male apolipoprotein E (ApoE) mice on a C57BL/6 background were randomly divided into control group and high fat diet group, 12 mice per group. The blood-lipid levels, the number of Foxp3CD4 CD25 T cells, and the size of the atherosclerotic lesions in every group were measured. The expression levels of Foxp3 in different tissues were detected. RESULTS: Compared with the control group, the level of plasma lipids was significantly higher in the high fat-fed group, but the number and function of Foxp3CD4 CD25 T cells, the levels of Foxp3 protein expression, and Foxp3 gene transcript in selected tissues were lower in the high fat-fed group. CONCLUSION: Hyperlipidemia inhibits the expression and function of Foxp3 in various immune organs, which may be one of the mechanisms by which hyperlipidemia aggravates the formation of atherosclerosis.

[Effects of MSCs on the progression of atherosclerosis plaque in ApoE-knock out mice].

AIM: To explore the effects of mesenchymal stem cells in the formation of atherosclerosis plaque in hypercholesterolemic apoliprotein (apo) E -/ - mice. METH-ODS: ApoE -- mice mesenchymal stem cells (MSCs)were isolated and identified. Thirty ApoE -/ - mice were divided into negative control group (Neg, n = 10), positive control group (Pos, n = 10) and MSCs group ( n = 10).MSCs were injected through caudal vein into the body ofPos and MSCs groups. The plaque area of all subjects were compared, the percentage of CD4 CD25' regulatory T cells in different tissues were analyzed by FACS, proliferation response of splenocytes to mesenchymal stem cells and cyto-kines in the supernatant were determined by ELISA. RE-SULTS: Compared with controls, MSCs resulted in a significant decrease of the atherosclerotic plaques size (P <0.05), and a significant increase of CD4 CD25 regulatory T cells in spleen (P<0.05). Specific proliferation response of CD4' CD25' regulatory T cells in splenocytes to MSCswas significantly suppressed. The supernatant levels ofTGF-f3 and IL-10 in MSCs group were increased while IFN-y decreased significantly. CONCLUSION: MSCs play an important role in regulating the inflammatory response and may significantly inhibit the formation of the atherosclerosis plaque in ApoE-'- mice.

In rats with myocardial infarction, interference by simvastatin with the TLR4 signal pathway attenuates ventricular remodelling.

OBJECTIVE: The objective of this study was to investigate the effect of simvastatin on TLR4,TNF-alpha and IL-6 expression in the myocardium and its relation to left ventricular (LV) remodelling in a rat model of myocardial infarction (MI) and to investigate the mechanism by which simvastatin improves LV remodelling in rats after MI. METHODS AND RESULTS: The rat MI models were established by ligation of the left anterior descending coronary artery and divided into three groups: (I) an untreated MI group; (2) a group treated with simvastatin [40 mg/(kg/d)] for 4 weeks; (3) the sham group. Cardiac geometry and function were determined by echocardiography and infarct size was determined by the histomorphometric analysis; the expression ofTLR4 in the myocardium was measured by RT-PCR and western blotting;TNF-alpha and IL-6 levels in myocardial homogenate and serum were measured by ELISA. LVEDD and LVESD significantly increased and fractional shortening (FS) markedly decreased in the MI group. It was clear that simvastatin inhibited LV dilation and improved LV function after MI without affecting infarct size. The expression of TLR4, TNF-alpha and IL-6 in the myocardium significantly increased in the MI group and simvastatin markedly inhibits the expression of TLR4, TNF-alpha, and IL-6 in the myocardium after MI. Serum TNF-alpha and IL-6 levels between the MI group and the simvastatin group remained unchanged. Both in the MI group and the simvastatin group,TLR4 protein positively related to LVEDD and to the levels of TNF-alpha and IL-6 in the myocardium, respectively. CONCLUSION: Amelioration of LV remodelling in rats after MI by simvastatin might be associated with its effect on the TLR4-mediated signalling pathway in the myocardium.