Achilles Pappano

Education

B.S., St. Joseph's College
Ph.D., University of Pennsylvania

Research interests

We are studying the mechanism(s) for the protective effect of an ATP receptor in a murine heart failure model. Transgenic cardiac overexpression of the calcium binding protein calsequestrin (CSQ) is associated with premature death. Endogenous ATP activates the P2X4 receptor (P2X4R), an ion channel receptor present in the mammalian heart. Overexpression of the human P2X4R is accompanied by increased contractile force in vivo and increased cell shortening in vitro. Transgenic animals that overexpress both the hP2X4R and CSQ are protected against heart failure; average life-span is increased by 4-5 weeks. Among the three factors regulating excitation-contraction coupling, we identified increased sarcoplasmic reticulum (SR) calcium content as contributing to the rescue effect. This effect is associated with increased intracellular calcium release by ATP. The increased SR calcium content stems from a reaction in which ATP promotes sodium entry via plasmalemmal P2X4R, the cell exchanges internal sodium for calcium at the sodium/calcium exchanger and the increased internal calcium is stored in the SR. Neither the L-type calcium current nor myofilament calcium sensitivity is affected by ATP when hP2X4R is overexpressed. Also, cAMP content is unaffected by ATP. In a heart failure model caused by ligation of the left anterior descending coronary artery, overexpression of the hP2X4R resulted in a greater contraction force and left ventricular developed pressure than in hearts from wild type mice and also increased survival at 1 and 2 months after ligation. There was no difference in the sizes of the infarcted tissue. Thus, rescue of animals from heart failure caused by two different means is ascribed to improved contractile performance dependent upon increased SR calcium.

Recent publications

Shen, J.B., and Pappano, A.J. 2008. An estrogen metabolite, 2-methoxyestradio, disrupts cardiac microtubules and unmasks muscarinic inhibition of calcium current. J. Pharmacol. Exp. Ther. 325: 507-512.

Shen, J.B., and Pappano, A.J. 2006. Extracellular ATP-stimulated current in wild-type and P2X4 receptor transgenic mouse ventricular myocytes: implications for a cardiac physiologic role of P2X4 receptors. FASEB J. 20: 277-284.

Gomez, A.M., Kerfant, B.G., Vassort, G., and Pappano, A.J. 2004. Autonomic regulation of calcium and potassium channels is oppositely modulated by microtubules in cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 286: H2065-2071.

Department of Cell Biology Faculty