Multiple signaling pathways coordinately mediate reactive oxygen species dependent cardiomyocyte 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.

A positive association between cardiomyocyte volume and serum malondialdehyde levels.

Cardiac hypertrophy is the first visible sign of cardiac remodeling. Oxidative stress is implicated in the etiopathogenesis of cardiac hypertrophy. In vitro studies have shown that exposure of cardiomyocytes to free radical generators induce cell hypertrophy. However, there are no studies to show that in vivo redox status can influence cardiomyocyte growth. Blood samples were collected from healthy volunteers and serum lipid peroxidation was determined as a measure of oxidative stress. Cardiac myocytes cultured from newborn rat were exposed to serum samples. A significant correlation was observed between serum lipid peroxidation and cardiomyocyte volume, indicating that in vivo oxidative stress can act as an important co-factor in mediating the hypertrophic response. This experimental system also envisages a novel approach to identify patients prone to left ventricular remodeling and identification of humoral factors mediating the changes.