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Chronic kidney disease (CKD) patients have deficient levels of circulating glutathione peroxidase 3 (GPx-3) protein. We hypothesized that GPx-3 deficiency may lead to a cardiomyopathy due to the accumulation of reactive oxygen species in the myocardium that enhances microvascular thrombosis and impairs microvascular perfusion. Using a proteomic screening platform we identified several circulating proteins of interest in 13 patients with CKD. Of the proteins detected, where greater than 20% of total polypeptide length was identified, GPx-3 was the most depressed low-abundance circulating protein. Patients with a cardiac event had on average a 70.8% decrease in GPx-3 plasma levels compared to similar CKD patients without a cardiac event (p=0.001). This finding was validated by western blot analysis and enzyme-linked immunoassay where GPx-3 levels were decreased by 54.4% (p=0.006) and 37.2% (p<0.001), respectively. To isolate the exclusive effect of GPx-3 deficiency in uremic cardiomyopathy, we studied the GPx-3 knockout mouse strain in the setting of surgeryinduced chronic kidney disease. GPx-3-/- and wild type mice were subject to nephron mass reduction surgery (NMR) followed by echocardiography 4 weeks after injury. Following NMR, fractional shortening was decreased to 32.9±5.8% in GPx-3-/- compared to 62.0%±10.3 (normal) in injured wildtypes (p<0.001). In vivo, platelet aggregates were increased in the myocardium after NMR and correlated with high levels of ADMA and low levels of GPx-3. In vitro platelet aggregation was enhanced in blood samples from GPx-3-/- undergoing NMR and was mitigated by clopidogrel. These results indicate GPx-3 deficiency as a potential substantive contributing factor for renal-induced cardiac disease, and offer an opportunity for targeted therapy.

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