Sodium Pump Isoforms in Xenotransplantation: Importance of Biochemical Compatibility

Abstract

Xenotransplantation of pig hearts to humans could be hampered by the reportedly reduced affinity for digoxin of pig heart. We examined the hypothesis that expression of the individual alpha-subunit isoforms of the sodium pump [Na(+),K(+)-ATPase (NKA)], the receptor for the plant-derived cardiac glycosides, may be responsible for this difference. We used a NKA-inhibition assay in combination with Western analysis, immunohistochemistry, and phosphorylation of the NKA alpha subunit to identify the distribution and expression of alpha isoforms in four chambers of porcine and human hearts. We confirmed that tissue from porcine heart is less sensitive to digitalis (IC(50) = 1740 nmol/L) when compared with human heart (IC(50) = 840 nmol/L), whereas porcine cerebral cortex-mix had an affinity comparable to that of human heart (IC(50) = 910 nmol/L). Our data show that porcine cerebral cortex-mix and human heart contain all three alpha isoforms, whereas porcine heart expresses only the alpha1 isoform. The different expressions of sodium pump isoforms in human vs porcine cardiac tissues suggests that porcine hearts may not be pharmacologically or endocrinologically compatible when used in humans. Studies of both pharmacologic and endocrinologic tissue compatibility are needed prior to selection of organs for xenotransplantation.