Calpain is a mediator of myocardial injury in experimental uremia: Is it activated by endogenous ouabain?

Abstract

Background. Incidence of cardiovascular disease is more than 20-fold higher in patients with chronic renal failure than in aged-matched individuals with normal renal function. Little is understood about the causes or the mechanism of uremia-induced cardiovascular injury, but the involvement of calpain as a possible mediator has recently been under investigation. Mean calpain activity was found to be 3.4-fold higher in the hearts of uremic rats than in control or spontaneously hypertensive (SHR) rats. In addition, calpain activity was found to be stimulated in myoblasts (Girardi) treated with media enriched with uremic serum compared with cells treated with serum from healthy volunteers. In this study, we assessed the impact of calpain activation in uremia and explored the possibility that calpain might be activated in uremia by endogenous ouabain. Ouabain is known to be elevated in uremia and is strongly associated with left ventricular hypertrophy in essential hypertension. Methods. Calpain activity was measured in situ in human-derived myoblasts treated with low doses of ouabain similar to those concentrations found in uremic patients. Results. Low concentrations of ouabain (10 nmol/L) caused a highly significant increase in calpain activity, which could be completely inhibited by the simultaneous chelation of intracellular and extracellular Ca2+, and by the chelation of extracellular Ca2+ alone. Conclusions. Calpain activity can be stimulated by nanomolar concentrations of ouabain due to an influx of extracellular Ca2+. As circulating ouabain is known to be elevated in uremia and strongly associated with LVH remodeling, we hypothesize that endogenous ouabain might be one of the factors that facilitates the remodeling of the left ventricle in patients with renal failure.