allopurinol and Hypertrophy

The heart responds to an increased demand arising due to physiological stimuli or pathological insults by hypertrophy of myocytes. Reactive oxygen species (ROS) have recently been identified as the molecular intermediates in the translation of mechanical stimuli to cellular response. Different signal transduction pathways have been implicated with cardiac hypertrophy, prominent among them being, mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and calcineurin. It remains unclear whether the ROS induced hypertrophy is mediated through one or more of these pathways. This study was taken up with the objective to affirm the role of ROS in the induction of cardiomyocyte hypertrophy and examine the contribution of specific pathways in the mediation of the hypertrophic response. The cellular response to enzyme-generated reactive oxygen species was examined in cultured cells from newborn rat heart. Pathway specific inhibitors were used to identify the role of each pathway in the mediation of cellular hypertrophy. Cellular hypertrophy in response to hypoxanthine-xanthine oxidase was prevented by inhibition of any one of the pathways; leading to the inference that oxidative stress induced hypertrophy is mediated by coordinative regulation of the three major pathways.

Topics: Animals; Animals, Newborn; Cell Size; Cells, Cultured; Hypertrophy; Hypoxanthine; Myocytes, Cardiac; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction; Superoxides; Xanthine Oxidase

Vascular xanthine oxidase (XO) activity has been found to be elevated in chronic vascular disease. Although a role for XO in endothelial dysfunction has been proposed, little is known about its influence on vascular smooth muscle maladaptive growth.. The proliferative and hypertrophic response of human aortic smooth muscle cells (HASMC) stimulated with xanthine/xanthine oxidase (X/XO) was quantified by determining cell number, cell size and protein synthesis. The levels and activity of the growth-related transcription factor activator protein 1 (AP-1) and the activation of mitogen-activated protein kinase (MAPK) by X/XO were determined by either Western blot or transient transfection experiments.. X/XO did not affect HASMC proliferation, but led to enhanced planar cell surface area and protein synthesis. In addition, X/XO enhanced c-jun levels and AP-1 transcriptional activity. Although X/XO did not modify extracellular signal-regulated protein kinases 1/2 MAPK or Akt/PKB activity, it promoted the activation of c-Jun N-terminal kinase and p38 MAPK, which were both necessary for X/XO to increase AP-1 activity and cell size in HASMC cultures. Finally, the effects of X/XO on MAPK activation, AP-1 activity and cell size were dependent on the extracellular release of superoxide anions through the enzymatic activity of XO, as they were prevented by both superoxide dismutase and allopurinol.. X/XO exhibits hypertrophic properties for human vascular smooth muscle, which are mediated by redox-sensitive pathways involving MAPK activation. XO can therefore participate in the maladaptive vascular remodeling observed in chronic cardiovascular diseases exhibiting elevated vascular XO activity.

Topics: Allopurinol; Aorta; Cell Enlargement; Cell Proliferation; Cells, Cultured; Humans; Hypertrophy; JNK Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Replication Protein C; Superoxides; Xanthine Oxidase

1. Nonenzymatic protein glycosylation is a possible mechanism contributing to oxidative stress and vascular disease in diabetes. In this work, the influence of 14%-glycosylated human oxyhaemoglobin (GHHb), compared to the non-glycosylated protein (HHb), was studied on several growth parameters of rat cultured vascular smooth muscle cells (VSMC). A role for reactive oxygen species was also analysed. 2. Treatment of VSMC for 48 h with GHHb, but not with HHb, increased planar cell surface area in a concentration dependent manner. The threshold concentration was 10 nM, which increased cell size from 7965+/-176 to 9411+/-392 microm2. Similarly, only GHHb enhanced protein content per well in VSMC cultures. 3. The planar surface area increase induced by 10 nM GHHb was abolished by superoxide dismutase (SOD; 50 200 u ml(-1)), deferoxamine (100 nM-100 microM), or dimethylthiourea (1 mM), while catalase (50 200 u ml(-1)) or mannitol (1 mM) resulted in a partial inhibition of cell size enhancement. 4. When a known source of oxygen free radicals was administered to VSMC, the xanthine/xanthine oxidase system, the results were analogous to those produced by GHHb. Indeed, enhancements of cell size were observed, which were inhibited by SOD, deferoxamine, or catalase. 5. These results indicate that, at low concentrations, GHHb induces hypertrophy in VSMC, this effect being mediated by superoxide anions, hydrogen peroxide, and/or hydroxyl radicals. Therefore, glycosylated proteins can have a role in the development of the structural vascular alterations associated to diabetes by enhancing oxidative stress.

Topics: Animals; Biomarkers; Cell Division; Glycated Hemoglobin; Humans; Hypertrophy; Muscle, Smooth, Vascular; Oxyhemoglobins; Rats; Rats, Sprague-Dawley; Serum Albumin; Xanthine Oxidase

Topics: Animals; Biochemistry; Creativity; History, 20th Century; Hyperplasia; Hypertrophy; Hypoxanthines; Kidney; Kidney Diseases; Mitosis; Pteridines; Purines; Pyrazines; Pyrimidines; Quinoxalines; Rats; Stimulation, Chemical; Structure-Activity Relationship; United Kingdom; Xanthine Oxidase; Xanthopterin

Topics: Animals; Chemical and Drug Induced Liver Injury; Chickens; Dietary Proteins; Hypertrophy; Kidney; Kidney Diseases; Kidney Function Tests; Liver; Male; Potassium; Protein Biosynthesis; Time Factors; Uric Acid; Xanthine Oxidase

Topics: Adenosine; Aminohydrolases; Growth; Hepatectomy; Hypertrophy; Liver; Liver Neoplasms; Nucleosides; Phosphotransferases; Rats; Research; Transferases; Xanthine Oxidase