Aerobic Exercise Attenuates Pressure Overload-Induced Myocardial Remodeling and Myocardial Inflammation via Upregulating miR-574-3p in Mice.

BACKGROUND: Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. METHODS: A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. RESULTS: Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). CONCLUSIONS: Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.

Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling.

Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 µM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor ß-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.

Cardiac-Specific Overexpression of Caveolin-1 in Rats With Ischemic Cardiomyopathy Improves Arrhythmogenicity and Cardiac Remodelling.

BACKGROUND: Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM. METHODS: ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodelling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter. RESULTS: Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spontaneous irregular proarrhythmogenic Ca2+ waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2+ cycling through normalizing Ca2+-handling protein levels and improving Ca2+ homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor-ß (TGF-ß)/Smad2 signalling pathway. Coimmunoprecipitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2+-handling protein levels. CONCLUSIONS: Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2+ cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2+-handling protein levels, improved Ca2+ homeostasis, and attenuated cardiac fibrosis.

[Effects of a novel spermine oxidase inhibitor SI-4650 on proliferation and EMT of human ovarian cancer SKVO-3 cells].

Objective: To investigate the effects of SI-4650, a novel small molecule inhibitor of spermine oxidase (SMO), on the proliferation and epithelial mesenchymal transformation (EMT) of human ovarian cancer SKVO-3 cells as well as its underlying molecular mechanisms. Methods: SKVO-3 cells treated with 0 µmol/L SI-4650 were used as control group, SKVO-3 cells treated with 30, 60 µmol/L SI-4650 were used as experimental group. The effects of SI-4650 on the activity of SMO, the polyamine contents and the cellular reactive oxygen species (ROS) were detected. Cell proliferation, cell cycle and mitochondrial membrane potential change of SKVO-3 cells were tested. The effects of SI-4650 on apoptosis, migration and invasion were investigated. The effects of SI-4650 on Bax, Bcl-2, Caspase3, E-cadherin, N-cadherin, Vimentin, matrix metalloproteinase 2 ( MMP2) and MMP 9 expression levels in SKVO-3 cells were detected. Results: Comparison between blank control group and experimental groups,SI-4650 could improve the content of SI-4650 in SKVO-3 cells. SI-4650 could inhibit the activity of SMO (P＜0.01), reduce the ROS (P＜0.01)and polyamine content in SKVO-3 cells (P＜0.01). Treatment of SKVO-3 cells with SI-4650 inhibited the proliferation (the inhibition rate was 32.27% and 47.31% in experimental groups), caused S-phase cell cycle arrest (P＜0.01) and induced apoptosis (P＜0.01). The expressions of Bax and c-Caspase3 in SKVO-3 cells were increased (P＜0.01),the content of Bcl-2 was decreased (P＜0.01), and the mitochondrial membrane potential was decreased (P＜0.01), and the number of apoptotic cells was increased(31.41% and 43.51% in experimental groups). At the same time, SI-4650 could change the expression levels of EMT-related factors, increased the expression level of E-cad , decreased the expression levels of N-cad, Vimentin, MMP-2 and MMP-9, and inhibited the migration and invasion of SKVO-3 cells. Conclusion: SI-4650 can effectively inhibit proliferation, invasion and metastasis of human ovarian cancer SKVO-3 cells, and the mechanism may be related to its ability to depress the activity of SMO, interfere polyamine metabolism and induce cell cycle arrest, mitochondrial apoptosis and inhibit EMT. This study reveals potential application of SI-4650 in the treatment of ovarian cancer.

Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum stress-mediated apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved caspase 3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 inhibitor EX527 (10 µM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.

The CD4+CD25 bright regulatory T cells and CTLA-4 expression in peripheral and decidual lymphocytes are down-regulated in human miscarriage.

The present study was undertaken to analyze the changes in the proportion of CD4(+)CD25(bright) regulatory T (Treg) cells and the expression of costimulatory molecules, CTLA-4 and CD28, in the peripheral blood and deciduas in the setting of non-pregnancy, normal early pregnancy and miscarriage. In this study, we showed that CD4(+)CD25(bright) T cells significantly increased in the peripheral of normal pregnancy compared to that of non-pregnancy. The proportions of CD4(+)CD25(bright) T cells in both peripheral blood and deciduas were significantly lower in miscarriage than that of normal pregnancy. CD4(+)CD25(bright) T cells were characterized by high-level FoxP3 expression and low-level CD69 expression. An increase in the CD28 mRNA expression was accompanied by a decrease in the CTLA-4 mRNA expression in decidual tissues from human miscarriage. The ratios of CTLA-4(+)/CD28(+) in miscarriage were significantly lower than that of the normal pregnancy both in the peripheral and in deciduas. The ratio of CTLA-4(+)/CD28(+) in CD4(+)CD25(bright) T cells was significantly higher than that of the CD4(+)CD25(dim) T cells both in normal pregnancy and in miscarriage. The decidual T cells in the miscarriage appeared higher in responsiveness and IL-2 and IFN-gamma production in comparison with the decidual T cells in the early pregnancy. These results above suggest that CD4(+)CD25(bright) Treg cells might play a role in the maintenance of pregnancy via up-regulation of CTLA-4 expression. The down-regulation of Treg cells and their functions, and the imbalance of positive and negative regulators of costimulatory signals might lead to an abnormal immune milieu, which confer susceptibility to pregnancy loss.