Signal‐transduction pathways in hemolysis‐associated right‐ventricular failure (1097.12)

• Published in: The FASEB journal Vol. 28; no. S1
• Main Author: Olonisakin, Tolani
• Format: Journal Article
• Language: English
• Published: The Federation of American Societies for Experimental Biology 01-04-2014
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.28.1_supplement.1097.12

The pulmonary arterial pressure at which the right ventricle fails in patients with sickle‐cell disease occurs at markedly lower pressures than in pulmonary hypertension not associated with hemolysis. The mechanism by which the right ventricle fails and the reason that dysfunction occurs at relatively low pulmonary arterial pressures in sickle‐cell disease remains poorly understood. Preliminary data from our group suggests that hemolysis, through activation of Ras homolog gene family member A (RhoA), causes activation of NADPH oxidase 2 (Nox2) and calcium/calmodulin‐dependent protein kinase II in the right ventricle leading to the production of reactive oxygen species, downstream mitochondrial destruction and ultimately, maladaptive remodeling of the right ventricle. We proceeded to examine whether RhoA activation indeed activates CaMKII via Nox2 and to see if this signaling axis drives myocyte dysfunction as evidenced by eNOS uncoupling and mitochondrial dysfunction. Six hours following exposure of rat neonatal cardiac myocytes (RNCM) to lysed red cell plasma resulted in a marked increase in superoxide production (P<0.01, n=15) that was significantly reduced by co‐incubation with the Nox2ds peptide (P<0.001). Bioenergetic analyses of RNCM showed a significant decrease in oxygen consumption rate after exposure to hemolyzed blood. Transfection studies showed an increase in RhoA expression after silencing Nox2 and CaMKII genes, suggesting that if RhoA is linked to these proteins, its activation may be upstream of Nox2 and CaMKII. Ongoing studies using peptide inhibitors are being employed to further elucidate the roles of the aforementioned proteins in hemolysis‐associated myocyte dysfunction.