LAUSR

Simple Summary Uric acid is a metabolite released by cells to detoxify themselves from nitrogen. Unlike other mammalians, hominids, and also birds, lack uricase, an enzyme that catalyzes the transformation of uric acid to allantoin. Therefore, high levels of uric acid accumulate in the plasma of hominids. Under certain conditions, i.e., the consumption of a fructose-rich diet, which is also often associated with diabetes, the concentrations of uric acid rise. Under such conditions, uric acid may in part exert effects on different cells. Using isolated and cultivated totally differentiated rat cardiomyocytes, we show that uric acid at plasma-relevant concentrations that are similar to those found in patients decreases the calcium-affinity of troponin in cardiomyocytes and thereby reduces cell function. Therefore, the accumulation of uric acid stresses cardiomyocytes, a mechanism that may contribute to heart failure under such conditions. Abstract Hyperuricemia is a risk factor for heart disease. Cardiomyocytes produce uric acid via xanthine oxidase. The enzymatic reaction leads to oxidative stress in uric-acid-producing cells. However, extracellular uric acid is the largest scavenger of reactive oxygen species, specifically to nitrosative stress, which can directly affect cells. Here, the effect of plasma-relevant concentrations of uric acid on adult rat ventricular cardiomyocytes is analyzed. A concentration- and time-dependent reduction of load-free cell shortening is found. This is accompanied by an increased protein expression of ornithine decarboxylase, the rate-limiting enzyme of the polyamine metabolism, suggesting a higher arginine turnover. Subsequently, the effect of uric acid was attenuated if other arginine consumers, such as nitric oxide synthase, are blocked or arginine is added. In the presence of uric acid, calcium transients are increased in cardiomyocytes irrespective of the reduced cell shortening, indicating calcium desensitization. Supplementation of extracellular calcium or stimulation of intracellular calcium release by β-adrenergic receptor stimulation attenuates the uric-acid-dependent effect. The effects of uric acid are attenuated in the presence of a protein kinase C inhibitor, suggesting that the PKC-dependent phosphorylation of troponin triggers the desensitizing effect. In conclusion, high levels of uric acid stress cardiomyocytes by accelerating the arginine metabolism via the upregulation of ornithine decarboxylase.