Search

We investigated sex differences and the role of estrogen receptor-[beta] (ER[beta]) on myocardial hypertrophy in a mouse model of pressure overload. We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER[beta] knockout (ER[[beta].sup.-/-]) mice. All mice were characterized by echocardiography and hemodynamic measurements and were killed 9 wk after surgery. Left ventricular (LV) samples were analyzed by microarray profiling, real-time RTPCR, and histology. After 9 wk, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. ER[beta] deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that WT male hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than WT female hearts. ER[[beta].sup.-/-] mice exhibited a different transcriptional response. ER[[beta].sup.-/-]/TAC mice of both sexes exhibited induction of proapoptotic genes with a stronger expression in ER[[beta].sup.-/-] males. Cardiac fibrosis was more pronounced in male WT/TAC than in female mice. This difference was abolished in ER[[beta].sup.-/-] mice. The number of apoptotic nuclei was increased in both sexes of ER[[beta].sup.-/-]/ TAC mice, most prominent in males. Female sex offers protection against ventricular chamber dilation in the TAC model. Both female sex and ER[beta] attenuate the development of fibrosis and apoptosis, thus slowing the progression to heart failure. heart failure doi: 10.1152/ajpregu.00825.2009.

Aims Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage. Methods and results Male 129/Sv mice received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. Five days prior to ISO application, oral Atglistatin (2 mmol/kg diet) or control treatment was started. Two and twelve days after the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days after the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, which was significantly improved by the application of Atglistatin. No changes in ejection fraction were observed. Further studies included histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, followed by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application induced subendocardial fibrosis and a profound pro-apoptotic cardiac response, as demonstrated using an apoptosis-specific gene expression-array. Atglistatin treatment led to a dramatic reduction of these pro-fibrotic and pro-apoptotic processes. We then identified a specific set of fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acid, palmitoleic acid, and oleic acid), which induced pro-apoptotic effects in cardiomyocytes. Atglistatin significantly blocked this adipocytic FA secretion. Conclusion This study demonstrates cardioprotective effects of Atglistatin in a mouse model of catecholamine-induced cardiac damage/dysfunction, involving anti-apoptotic and anti-fibrotic actions. Notably, beneficial cardioprotective effects of Atglistatin are likely mediated by non-cardiac actions, supporting the concept that pharmacological targeting of adipose tissue may provide an effective way to treat cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some patients. A non-HLA, anogiotensin II type 1 [AT(sub 1)] -receptor-mediated pathway might contribute to refractory vascular rejection, and affected patients might benefit from removal of [AT(sub 1)] -receptor antibodies or from pharmocologic blockade of [AT(sub 1)] receptors.

Peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPAR[gamma] activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPAR[gamma] function in glucose and insulin homeostasis is still unclear. Recently, the function of PPAR[gamma] in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPAR[gamma] in those tissues. In those studies, adipose PPAR[gamma], has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. Two major mechanisms have been described. 1) Adipose PPAR[gamma] protects nonadipose tissue against excessive lipid overload and maintains normal organ function (liver, skeletal muscle); and 2) adipose PPAR[gamma] guarantees a balanced and adequate production of secretion from adipose tissue of adipocytokines such as adiponectin and leptin, which are important mediators of insulin action in peripheral tissues. In contrast to studies in adipose-specific PPAR[gamma]-deficient mice, the data in muscle-specific PPAR[[gamma].sup.-/-] mice demonstrate that whole body insulin sensitivity is, at least in part, relying on an intact PPAR[gamma] system in skeletal muscle. Finally, these early and elegant studies using tissue-specific PPAR[gamma] knockout mouse models pinpoint adipose tissue as the major target of TZD-mediated improvement of hyperlipidemia and insulin sensitization. peroxisome proliferator-activated receptor-[gamma]; diabetes; glitazone

BACKGROUND Resistance to diamide insecticides in Lepidoptera is known to be caused primarily by amino acid changes on the ryanodine receptor (RyR). Recently, two new target site mutations, G4946V and I4790M, have emerged in populations of diamondback moth, Plutella xylostella, as well as in other lepidopteran species, and both mutations have been shown empirically to decrease diamide efficacy. Here, we quantify the impact of the I4790M mutation on diamide activation of the receptor, as compared to alterations at the G4946 locus. RESULTS: I4790M when introduced into P. xylostella RyR expressed in an insect‐derived Sf9 cell line was found to mediate just a ten‐fold reduction in chlorantraniliprole efficacy (compared to 104‐ and 146‐fold reductions for the G4946E and G4946V variants, respectively), whilst in the field its presence is associated with a ≥150‐fold reduction. I4790M‐mediated resistance to flubendiamide was estimated to be >24‐fold. When the entire coding sequence of P. xylostella RyR was integrated into Drosophila melanogaster, the I4790M variant conferred ~4.4‐fold resistance to chlorantraniliprole and 22‐fold resistance to flubendiamide in the 3rd instar larvae, confirming that it imparts only a moderate level of resistance to diamide insecticides. Although the I4790M substitution appears to bear no fitness costs in terms of the flies' reproductive capacity, when assessed in a noncompetitive environment, it does, however, have potentially major impacts on mobility at both the larval and adult stages. CONCLUSIONS: I4790M imparts only a moderate level of resistance to diamide insecticides and potentially confers significant fitness costs to the insect. [ABSTRACT FROM AUTHOR]