inositol-1-4-5-trisphosphate and Hypertrophy

Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca2+]i-rise caused by 3 h of Fas activation are dependent on the Fas-->phospholipase C (PLC)-->1,4,5-inositol trisphosphate (1,4,5-IP3)-->sarcoplasmic reticulum (SR) [Ca2+]i release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy.. The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence.. Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP3R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP3 pathway), genistein and by the PI3K blocker LY294002.. Fas-mediated hypertrophy is dependent on the 1,4,5-IP3 pathway, which is functionally inter-connected to the PI3K/AKT/GSK3beta pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy.

Topics: Animals; Animals, Newborn; Apoptosis; Calcium-Transporting ATPases; Cardiomegaly; Cell Membrane; Cells, Cultured; fas Receptor; Fluorescent Antibody Technique; Hypertrophy; Immunoblotting; Inositol 1,4,5-Trisphosphate; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Sodium-Calcium Exchanger

The balance between the two major second messenger systems in hypertrophied myocardium was studied in rats receiving panangin for 16 days. Panangin producing stimulating and polarizing effects on cardiomyocyte membrane improved electrophysiological characteristics of hypertrophied myocardium (electrical stability, duration of supernormal excitability period, and action potential), activated the phosphoinositide exchange, and inhibited the adenylate cyclase system. The panangin-induced change in membrane potentials was accompanied by a pronounced inositol response, i.e. a decrease in the content of membrane polyphosphoinositides (phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-biphosphate) in the brain. It was concluded that function of ion channels depends on activity of phosphoinositide- and adenylate cyclase second messengers systems.

Topics: Animals; Aorta; Brain; Cardiotonic Agents; Cyclic AMP; Hypertrophy; Inositol 1,4,5-Trisphosphate; Ions; Membrane Potentials; Myocardium; Potassium Magnesium Aspartate; Rats; Signal Transduction; Time Factors

The mammalian anx7 gene codes for a Ca(2+)-activated GTPase, which supports Ca(2+)/GTP-dependent secretion events and Ca(2+) channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca(2+) signaling in secreting pancreatic beta cells, we knocked out the anx7 gene in the mouse and tested the insulin-secretory properties of the beta cells. The nullizygous anx7 (-/-) phenotype is lethal at embryonic day 10 because of cerebral hemorrhage. However, the heterozygous anx7 (+/-) mouse, although expressing only low levels of ANX7 protein, is viable and fertile. The anx7 (+/-) phenotype is associated with a substantial defect in insulin secretion, although the insulin content of the islets, is 8- to 10-fold higher in the mutants than in the normal littermate control. We infer from electrophysiological studies that both glucose-stimulated secretion and voltage-dependent Ca(2+) channel functions are normal. However, electrooptical recordings indicate that the (+/-) mutation has caused a change in the ability of inositol 1,4,5-trisphosphate (IP(3))-generating agonists to release intracellular calcium. The principle molecular consequence of lower anx7 expression is a profound reduction in IP(3) receptor expression and function in pancreatic islets. The profound increase in islets, beta cell number, and size may be a means of compensating for less efficient insulin secretion by individual defective pancreatic beta cells. This is a direct demonstration of a connection between glucose-activated insulin secretion and Ca(2+) signaling through IP(3)-sensitive Ca(2+) stores.

Topics: Animals; Annexin A7; Calcium; Calcium Channels; Calcium Signaling; Cell Line; Cytosol; Electrophysiology; Genetic Vectors; Glucose; GTP Phosphohydrolases; Hyperplasia; Hypertrophy; Immunohistochemistry; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Knockout; Mutagenesis; Phenotype; Receptors, Cytoplasmic and Nuclear