Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3,5-diiodothyropropionic acid (DITPA)

Heart failure of diverse causes is associated with abnormalities of sarcopl asmic reticulum (SR) Ca2+ transport. The purpose of this study was to deter mine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (D ITPA), prevents abnormal Ca2+ transport add expression of SR proteins assoc iated with post-infarction heart failure. New Zealand White rabbits were ra ndomly assigned to circumflex artery ligation or sham operation, and to DIT PA administration (3.75 mg/kg/day) or no treatment in a two-by-two factoria l design. After 3 weeks, echo-Doppler and LV hemodynamic measurements were performed. From ventricular tissue, single myocyte shortening and relaxatio n were determined, and Ca2+ transport was measured in homogenates and SR-en riched microsomes, Levels of mRNA and protein content were determined for t he SR Ca2+-ATPase (SERCA2a), phospholamban (PLB), cardiac ryanodine recepto r (RyR-2) and calsequestrin. The administration of DITPA improved LV contra ction and relaxation and improved myocyte shortening in infarcted animals. The improvements in LV and myocyte function were associated with increases in V-max for SR Ca2+ transport in both homogenates and microsomes. Also, DI TPA prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2 post-infarction, without measurable changes in mRNA levels. The thyroid ho rmone analogue, DITPA, improves LV, myocyte and SR function in infarcted he arts and prevents the downregulation of SR proteins associated with post-in farction heart failure. The specific effects of DITPA on post-infarction SR Ca2+ transport and the expression of SR proteins make this compound a pote ntially useful therapeutic agent for LV systolic and/or diastolic dysfuncti on. (C) 2000 Academic Press.