Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload.

Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.

[Multi-factor model of quality of life in patients with acute coronary syndrome].

OBJECTIVE: To detect the risk factors of quality of life (QOL) in patients with acute coronary syndrome (ACS), so as to help doctors to recognize the risk population with impaired QOL. METHODS: 403 hospitalized ACS patients, 252 males and 151 females, aged 67 12, 168 with ST-segment elevation myocardial infarction (STEMI), 4 with non-ST-segment elevation myocardial infarction (NSTEMI), and 74 with unstable angina pectoris (UAP), were surveyed with short-form-36 (SF-36) scale (Chinese version), including physical component summary (PCS) and mental component summary (MCS) so as to analyze the QOL, hospital anxiety depression scales (HADS) so as to detect the anxiety status. Multiple linear regression analysis was conducted to identify the variables associated with QOL. RESULTS: Of the 403 patients 84 (20.8%) suffered from anxiety, 43 (10.7%) suffered from depression, and 144 (35.7%) suffered from depression combined with anxiety symptoms . Age (r = -0.237, P < 0.001), being female (r = -0.183, P < 0.001), depression (r = -0.180; P < 0.001), and anxiety (r = -0.211, P <0. 001) were independent risk factors of physical QOL. Age (r = -0.117, P = 0.01), depression (r =-0.169, P = 0.004), and anxiety (r = -0.215, P < 0.001) were independently negatively correlated with mental QOL. Smoking was unexpectedly a protective factor for MCS (r = 0.157, P = 0.001). CONCLUSION: Depression and anxiety are common in patients diagnosed as with ACS, and appear to be related to significant worsening of QOL. The patients being female, with elder age, and suffering from depression and/or anxiety may be with impaired QOL, and need more care and effective intervention.

[The relation between post-acute coronary syndrome anxiety and serum levels of inflammatory factors].

OBJECTIVE: To explore the role of inflammatory factors (interleukin-6, tumor necrosis factor alpha, high sensitive C reactive protein) in the pathogenesis of anxiety after acute coronary syndrome (ACS) by investigating the serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha) and high sensitive C reactive protein (hsCRP). METHODS: Serum IL-6, TNFalpha and hsCRP levels were measured in 105 ACS patients within 7 days after onset of the event. Symptoms of anxiety were evaluated by self-reporting standardized questionnaire, using a validated Chinese version of Hospital Anxiety and Depression Scale (HADS-A)-Anxiety Subscale (7 items) within 72 hours of the event. Demographic and clinical data including cardiac risk factors were recorded. RESULTS: The median of TNFalpha was lower in the anxious patients with ACS than that of non-anxious ones (44.55 vs 61.70, P = 0.004). Neither the levels of hsCRP nor the levels of IL-6 were found to be different between the groups with anxiety and without. CONCLUSION: Anxiety after ACS does not increase the inflammatory reaction in the ACS patients.

Growth Arrest-Specific 6 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy.

Growth arrest-specific 6 (GAS6) is a member of the vitamin K-dependent protein family that is involved in the regulation of the cardiovascular system, including vascular remodeling, homeostasis, and atherosclerosis. However, there is still no study that systemically elucidates the role of GAS6 in cardiac hypertrophy. Here, we found that GAS6 was upregulated in human dilated cardiomyopathic hearts, hypertrophic murine hearts, and angiotensin II-treated cardiomyocytes. Next, we examined the influence of GAS6 expression in response to a cardiac stress by inducing chronic pressure overload with aortic banding in wild-type and GAS6-knockout mice or cardiac-specific GAS6 overexpressing mice. Under basal conditions, the GAS6-knockout mice had normal left ventricular structure and function but after aortic banding, the mice demonstrated less hypertrophy, fibrosis, and contractile dysfunction when compared with wild-type mice. Conversely, cardiac-specific overexpression of GAS6 exacerbated aortic banding-induced cardiac hypertrophy, fibrosis, and dysfunction. Furthermore, we demonstrated that GAS6 activated the mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 pathway during pressure overload-induced cardiac hypertrophy, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed GAS6 overexpression-induced cardiac hypertrophy and fibrosis, resulting in improved cardiac function. Collectively, our data support the notion that GAS6 impairs ventricular adaptation to chronic pressure overload by activating mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 signaling. Our findings suggest that strategies to reduce GAS6 activity in cardiac tissue may be a novel approach to attenuate the development of congestive heart failure.

Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload-Induced Pathological Cardiac Hypertrophy.

BACKGROUND: Smad nuclear interacting protein 1 (SNIP1) plays a critical role in cell proliferation, transformation of embryonic fibroblasts, and immune regulation. However, the role of SNIP1 in cardiac hypertrophy remains unclear. METHODS AND RESULTS: Here we examined the role of SNIP1 in pressure overload-induced cardiac hypertrophy and its mechanisms. Our results demonstrated that SNIP1 expression was downregulated in human dilated cardiomyopathic hearts, aortic banding-induced mice hearts, and angiotensin II-treated cardiomyocytes. Accordingly, SNIP1 deficiency significantly exacerbated aortic banding-induced cardiac hypertrophy, fibrosis, and contractile dysfunction, whereas cardiac-specific overexpression of SNIP1 markedly recovered pressure overload-induced cardiac hypertrophy and fibrosis. Besides that, SNIP1 protected neonatal rat cardiomyocytes against angiotensin II-induced hypertrophy in vitro. Moreover, we identified that SNIP1 suppressed nuclear factor-κB signaling during pathological cardiac hypertrophy, and inhibition of nuclear factor-κB signaling by a cardiac-specific conditional inhibitor of κBS32A/S36A transgene blocked these adverse effects of SNIP1 deficiency on hearts. CONCLUSIONS: Together, our findings demonstrated that SNIP1 had protective effects in pressure overload-induced pathological cardiac hypertrophy via inhibition of nuclear factor-κB signaling. Thus, SNIP1 may be a novel approach for the treatment of heart failure.

Association of TCF7L2 gene polymorphisms with type 2 diabetes mellitus in Han Chinese population: a meta-analysis.

Variants of transcription factor 7-like 2 (TCF7L2) gene have been reported to be associated with type 2 diabetes mellitus (T2DM), but the available data on this relationship are inconsistent in Han Chinese populations. A meta-analysis was performed to quantitatively analyze the association of TCF7L2 gene polymorphisms with T2DM using previous case-control studies in Chinese Han populations. Several electronic databases were searched for relevant articles up to May 2012. After data collection and gene loci selection, a meta-analysis was performed to assess heterogeneity, combine results and evaluate variations. Publication bias was examined by the Egger's linear regression test. Hardy-Weinberg equilibrium (HWE) test and by omitting one study at a time were employed for the sensitivity analysis. Eighteen studies from sixteen eligible papers were included in the meta-analysis. Ten eligible studies were analyzed for rs7903146, and eight were analyzed for rs290487. We found that the rs7903146 T allele was associated with an increased risk for T2DM under a dominant model, a co-dominant model and an allele contrast model, with an OR of 1.54 (1.32, 1.79), an OR of 1.53 (1.31, 1.79) and an OR of 1.52 (1.31, 1.76), respectively. The rs290487 C allele showed no significant overall association with T2DM, yielding ORs of 1.08 (0.88, 1.32) under a dominant model, with strong evidence of heterogeneity. Similar results were also obtained in other genetic models. Sensitivity analysis confirmed the reliability and stability of this meta-analysis. The accumulated evidence suggested that the rs7903146 T allele was associated with an increased risk for T2DM, but the rs290487 C allele is not associated with T2DM in the Chinese Han population. More well-designed large studies are required for the validation of this association.

Tesaglitazar ameliorates non-alcoholic fatty liver disease and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient mice.

Previous research has demonstrated that the dual PPARα/γ agonist tesaglitazar reduces atherosclerosis in a mouse model of hyperlipidemia by reducing both lipid content and inflammation in the aorta. However, much of the underlying mechanism of tesaglitazar in non-alcoholic fatty liver disease (NAFLD) remains less clear. The aim of the present study was to determine whether tesaglitazar attenuates NAFLD and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient (LDLr(-/-)) mice. Female LDLr(-/-) mice (3 weeks old) were induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection to develop an animal model of type 2 diabetes (T2DM). The mice were randomly divided into two groups: diabetic group (untreated diabetic mice, n=15) and tesaglitazar therapeutic group (n=15, 20 µg/kg/day oral treatment for 6 weeks). Fifteen LDLr(-/-) mice were fed with an HFD as the control group. Tesaglitazar decreased serum glucose and lipid levels compared with the diabetic mice. Tesaglitazar significantly reduced atherosclerotic lesions, lipid accumulation in the liver, macrophage infiltration, and decreased total hepatic cholesterol and triglyceride content compared to the diabetic mice. In addition, tesaglitazar reduced inflammatory markers at both the serum and mRNA levels. Our data suggest that tesaglitazar may be effective in preventing NAFLD and atherosclerosis in a pre-existing diabetic condition by regulating glucose and lipid metabolism, and the inflammatory response.