The Role Of Nitric Oxide And Adrenomedullin In Cardiovascular Failure In Septic Shock PDF Download

Abstract: The primary focus of this work is to investigate the role of nitric oxide control in cardiac and endothelial dysfunction. Intact endothelial function is a major regulator of cardiovascular function. Alterations in nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS, NOS3) have been implicated in cardiovascular dysfunction. NOS3 genetic polymorphisms have been linked to enhanced cardiovascular disease risk but functional implications are not identified. We tested the hypothesis that the NOS3 Glu298Asp polymorphism is associated with altered endothelial cell functional responses with respect to wound healing, responses to high shear, toxic stress and altered protein-protein interactions. We provide the first evidence that presence of NOS3 exon7 Glu298Asp polymorphism alters the endothelial cell (EC) responses to high shear. These alterations are due to differences in interactions between NOS3 and Cav-1. The NOS3 Glu298Asp polymorphism significantly delays the wound closure response in ECs. Moreover, these effects were significantly altered by different VEGF isoforms. Genetic polymorphisms in NOS3 gene and ACE gene have been identified and linked to enhanced vascular susceptibility. We demonstrate the functional importance of NOS3 genetic polymorphism but not the ACE genetic polymorphism. In this section we provide first time evidence for a role of NOS3 Glu298Asp polymorphism in EC function. Reactive oxygen and nitrogen species and mitochondrial dysfunction have all been individually implicated in sepsis related organ failure. Their roles in cardiac failure associated with sepsis are less completely understood. We developed a novel method for measuring mitochondrial morphological alterations and tested the hypothesis that increased NO production and altered mitochondrial functions are implicated as contributing mechanisms to sepsis-induced cardiac dysfunction. We also investigated the potential role of calcineurin inhibitors in attenuation of dysfunction. LPS treatment resulted in reduced contractility and prolonged relaxation times, altered myocardial mitochondrial morphology, and increases in NOS2 protein expression and protein nitration. Enhanced myocardial protein nitration was associated with increased mitochondrial swelling and cardiac dysfunction. Thus, altered reactive nitrogen species apparently play an important role in sepsis related cardiac failure. Moreover, calcineurin inhibitors attenuated the sepsis related dysfunction, providing preliminary evidence for their role as potential therapeutic strategy in sepsis-related organ failure.