Amelioration of desmin network defects by αB-crystallin overexpression confers cardioprotection in a mouse model of dilated cardiomyopathy caused by LMNA gene mutation.

The link between the cytoplasmic desmin intermediate filaments and those of nuclear lamins serves as a major integrator point for the intracellular communication between the nucleus and the cytoplasm in cardiac muscle. We investigated the involvement of desmin in the cardiomyopathy caused by the lamin A/C gene mutation using the LmnaH222P/H222P mouse model of the disease. We demonstrate that in these mouse hearts desmin loses its normal Z disk and intercalated disc localization and presents aggregate formation along with mislocalization of basic intercalated disc protein components, as well as severe structural abnormalities of the intercalated discs and mitochondria. To address the extent by which the observed desmin network defects contribute to the progression of LmnaH222P/H222P cardiomyopathy, we investigated the consequences of desmin-targeted approaches for the disease treatment. We showed that cardiac-specific overexpression of the small heat shock protein αΒ-Crystallin confers cardioprotection in LmnaH222P/H222P mice by ameliorating desmin network defects and by attenuating the desmin-dependent mislocalization of basic intercalated disc protein components. In addition, αΒ-Crystallin overexpression rescues the intercalated disc, mitochondrial and nuclear defects of LmnaH222P/H222P hearts, as well as the abnormal activation of ERK1/2. Consistent with that, by generating the LmnaH222P/H222PDes+/- mice, we showed that the genetically decreased endogenous desmin levels have cardioprotective effects in LmnaH222P/H222P hearts since less desmin is available to form dysfunctional aggregates. In conclusion, our results demonstrate that desmin network disruption, disorganization of intercalated discs and mitochondrial defects are a major mechanism contributing to the progression of this LMNA cardiomyopathy and can be ameliorated by αΒ-Crystallin overexpression.

Intermediate filaments in cardiomyopathy.

Intermediate filament (IF) proteins are critical regulators in health and disease. The discovery of hundreds of mutations in IF genes and posttranslational modifications has been linked to a plethora of human diseases, including, among others, cardiomyopathies, muscular dystrophies, progeria, blistering diseases of the epidermis, and neurodegenerative diseases. The major IF proteins that have been linked to cardiomyopathies and heart failure are the muscle-specific cytoskeletal IF protein desmin and the nuclear IF protein lamin, as a subgroup of the known desminopathies and laminopathies, respectively. The studies so far, both with healthy and diseased heart, have demonstrated the importance of these IF protein networks in intracellular and intercellular integration of structure and function, mechanotransduction and gene activation, cardiomyocyte differentiation and survival, mitochondrial homeostasis, and regulation of metabolism. The high coordination of all these processes is obviously of great importance for the maintenance of proper, life-lasting, and continuous contraction of this highly organized cardiac striated muscle and consequently a healthy heart. In this review, we will cover most known information on the role of IFs in the above processes and how their deficiency or disruption leads to cardiomyopathy and heart failure.

Plasma proteomic analysis in obese and overweight prepubertal children.

BACKGROUND: Childhood obesity represents one of the most challenging health problems of our century and is associated with significant morbidity and mortality in adult life. Proteomics is a large-scale analysis of proteins, which provides, information on protein expression levels, post-translational modifications, subcellular localization and interactions. OBJECTIVE: To investigate whether obesity in childhood is associated with alterations in plasma protein expression profiles. METHODS: Plasma samples from 10 obese [age: 10·75 ± 0·16 year; body mass index (BMI): 27·50 ± 0·69 kg m(-2) ], 10 overweight (age: 10·54 ± 0·1 year; BMI: 21·88 ± 0·28 kg m(-2) ) and 10 normal-weight (age: 10·89 ± 0·19 year; BMI: 18·34 ± 0·42kg m(-2) ) prepubertal boys were subjected to protein fractionation and analysed by two-dimensional electrophoresis, followed by protein identification using matrix-assisted laser desorption time-of-flight mass spectrometry. Fasting plasma glucose and serum insulin, lipid and apolipopoprotein concentrations were determined in all subjects. RESULTS: The expression of apolipoprotein (Apo) A-I (ApoA-I) was significantly lower in obese and overweight children compared with children of normal BMI (P < 0·05). The expression of ApoE was significantly lower in overweight compared with normal-weight children (P < 0·05), while that of ApoA-IV was significantly higher in obese children compared with their normal counterparts (P < 0·01). Serum ApoA-I concentrations were significantly lower in obese (147 ± 4·27mg dL(-1) ) and overweight (145·5 ± 9·65mg dL(-1) ) than in normal-weight (157 ± 8·77mg dL(-1) ; P = 0·036) children. CONCLUSIONS: Obese and overweight prepubertal children demonstrated prominent alterations in the expression of plasma apolipoproteins compared with their normal counterparts. Low ApoA-I plasma expression levels and serum concentrations in obesity might be present in childhood before any significant alterations in total or high-density lipoprotein-cholesterol concentrations are documented. We recommend that serum ApoA-I concentrations are determined in all overweight and obese children.

The human glucocorticoid receptor: molecular basis of biologic function.

The characterization of the subfamily of steroid hormone receptors has enhanced our understanding of how a set of hormonally derived lipophilic ligands controls cellular and molecular functions to influence development and help achieve homeostasis. The glucocorticoid receptor (GR), the first member of this subfamily, is a ubiquitously expressed intracellular protein, which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes. The effector domains of the GR mediate transcriptional activation by recruiting coregulatory multi-subunit complexes that remodel chromatin, target initiation sites, and stabilize the RNA-polymerase II machinery for repeated rounds of transcription of target genes. This review summarizes the basic aspects of the structure and actions of the human (h) GR, and the molecular basis of its biologic functions.