3‐Iodothyronamine is a novel suppressor of fetal sheep cardiomyocyte proliferation in vitro

Abstract

OBJECTIVES:Fetal cardiomyocyte (CMC) maturation results in cells losing ability to divide. In late‐gestation sheep CMCs thyroid hormone (T3) decreased proliferation and changed signaling protein levels in favor of cell cycle arrest (Chattergoon et al, 2007). 3‐Iodothyronamine (T1AM) is a naturally occurring relative of T3 that does not bind classical thyroid receptors (TRs). We hypothesized that T1AM may depress CMC proliferation similar to T3.METHODS:Isolated right and left ventricular fetal sheep CMCs were cultured with T1AM (1nM, 10nM) and Bromodeoxyuridine (BrdU; 10μM) for 48 hours. Two ages were studied—100 days gestational age (dGA) and 135dGA—to determine developmental variations. BrdU uptake (index of proliferation) in fixed cells was analyzed.RESULTS:Basal BrdU uptake in serum free medium (SFM) was 10–12% in 100dGA CMCs versus 1–2% in 135dGA CMCs (p<0.01). BrdU uptake in response to 10% serum medium (SM) increased to 20% in 100dGA cells versus 8–10% in 135dGA CMCs (p<0.01). Similar to T3, T1AM does not affect cells exposed to SFM but decreases BrdU uptake by CMCs exposed to SM by 50% (p<0.05).CONCLUSIONS:These data suggest T1AM is as potent an inhibitor of fetal CMC proliferation as T3. Because T1AM does not activate TRs, non‐classical signaling of T1AM and T3 may be important in CMC growth and maturation.Grant support: NICHD (P01HD34430) and Minority Supplement (3PO1 HD034430‐09S1).