betadex and Hypertrophy

Our findings indicate that in ovariectomized female rats abdominal aortic constriction led to significant increases in left ventricular mass, myocyte diameter and heart weight/body weight (HW/BW) value, and decreases in interventricular septal thickness at diastole (IVSd), left ventricular percent fractional shortening (FS) and ejection fraction (EF). These pathophysiological alterations were largely reversed by administration with 17β-estradiol for eight weeks. Furthermore, the enhanced expression of extracellular signal-regulated kinases 1/2 and decreased expression of caveolin-3 were found in left ventricle of AAC group. 17β-estradiol (E(2)) administration increased the expression of caveolin-3 and reduced the level of ERK phosphorylation in these pressure-overloaded rats. Moreover, in cultured neonatal rat cardiomyocytes, E(2) inhibited the hypertrophic response to angiotensin II. This effect was reinforced by the addition of extracellular signal-regulated kinases 1/2 inhibitor PD98059, but was impaired when the cells were pretreated with caveolae disruptor, methyl-β-cyclodextrin (M-β-CD). In conclusion, our data indicate that estrogen attenuates the hypertrophic response induced by pressure overload through down-regulation of extracellular signal-regulated kinases 1/2 phosphorylation and up-regulation of caveolin-3 expression.

Topics: Animals; beta-Cyclodextrins; Blotting, Western; Caveolae; Caveolin 3; Electrocardiography; Estradiol; Extracellular Signal-Regulated MAP Kinases; Female; Hypertrophy; Myocardium; Ovariectomy; Pressure; Rats; Rats, Sprague-Dawley

A metalloprotease, ADAM17, mediates the generation of mature ligands for the epidermal growth factor receptor (EGFR). This is the key signaling step by which angiotensin II (AngII) induces EGFR transactivation leading to hypertrophy and migration of vascular smooth muscle cells (VSMCs). However, the regulatory mechanism of ADAM17 activity remains largely unclear. Here we hypothesized that caveolin-1 (Cav1), the major structural protein of a caveolae, a membrane microdomain, is involved in the regulation of ADAM17. In cultured VSMCs, infection of adenovirus encoding Cav1 markedly inhibited AngII-induced EGFR ligand shedding, EGFR transactivation, ERK activation, hypertrophy and migration, but not intracellular Ca(2+) elevation. Methyl-β-cyclodextrin and filipin, reagents that disrupt raft structure, both stimulated an EGFR ligand shedding and EGFR transactivation in VSMCs. In addition, non-detergent sucrose gradient membrane fractionations revealed that ADAM17 cofractionated with Cav1 in lipid rafts. These results suggest that lipid rafts and perhaps caveolae provide a negative regulatory environment for EGFR transactivation linked to vascular remodeling induced by AngII. These novel findings may provide important information to target cardiovascular diseases under the enhanced renin angiotensin system.

Topics: ADAM Proteins; ADAM17 Protein; Angiotensin II; Animals; beta-Cyclodextrins; Calcium; Caveolin 1; Cell Movement; Cells, Cultured; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Filipin; Gene Transfer Techniques; Hypertrophy; Membrane Microdomains; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction; Transcriptional Activation; Ventricular Remodeling

Enlarged fat cells exhibit modified metabolic capacities, which could be involved in the metabolic complications of obesity at the whole body level. We show here that sterol regulatory element-binding protein 2 (SREBP-2) and its target genes are induced in the adipose tissue of several models of rodent obesity, suggesting cholesterol imbalance in enlarged adipocytes. Within a particular fat pad, larger adipocytes have reduced membrane cholesterol concentrations compared with smaller fat cells, demonstrating that altered cholesterol distribution is characteristic of adipocyte hypertrophy per se. We show that treatment with methyl-beta-cyclodextrin, which mimics the membrane cholesterol reduction of hypertrophied adipocytes, induces insulin resistance. We also produced cholesterol depletion by mevastatin treatment, which activates SREBP-2 and its target genes. The analysis of 40 adipocyte genes showed that the response to cholesterol depletion implicated genes involved in cholesterol traffic (caveolin 2, scavenger receptor BI, and ATP binding cassette 1 genes) but also adipocyte-derived secretion products (tumor necrosis factor alpha, angiotensinogen, and interleukin-6) and proteins involved in energy metabolism (fatty acid synthase, GLUT 4, and UCP3). These data demonstrate that altering cholesterol balance profoundly modifies adipocyte metabolism in a way resembling that seen in hypertrophied fat cells from obese rodents or humans. This is the first evidence that intracellular cholesterol might serve as a link between fat cell size and adipocyte metabolic activity.

Topics: 3T3 Cells; Adipocytes; Adipose Tissue; Animals; beta-Cyclodextrins; Carboxypeptidase H; Carboxypeptidases; Carrier Proteins; Cell Membrane; Cells, Cultured; Cholesterol; Cyclodextrins; DNA-Binding Proteins; Energy Metabolism; Epididymis; Gene Expression Regulation; Glucose; Humans; Hydroxymethylglutaryl CoA Reductases; Hypertrophy; Insulin; Male; Membrane Lipids; Mice; Mice, Knockout; Mice, Obese; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, LDL; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sterol Regulatory Element Binding Protein 2; Transcription Factors