Dose-dependent effects of thyroid hormone on post-ischemic cardiac performance: potential involvement of Akt and ERK signalings Iordanis Mourouzis • Polixeni Mantzouratou • Georgios Galanopoulos • Erietta Kostakou • Nikolaos Roukounakis • Alexandros D. Kokkinos • Dennis V. Cokkinos • Constantinos Pantos Received: 16 September 2011 / Accepted: 24 November 2011 / Published online: 2 December 2011 Ó Springer Science+Business Media, LLC. 2011 Abstract The present study explored the effects of thy- roid hormone (TH) treatment on post-ischemic cardiac function and potential implicated mechanisms. Acute myocardial infarction (AMI) was induced in mice by cor- onary artery ligation while sham-operated animals served as controls. This procedure resulted in a marked depression of cardiac function and significant reduction in TH levels in plasma. TH was given at a dose aiming to normalize T3 levels in plasma [AMI-TH (A)] and also at higher doses. The group of animals treated with the highest dose of TH, which displayed significantly increased mortality rate was included in the study [AMI-TH (B)]. In AMI-TH (A) mice, TH significantly improved left ventricular (LV) ejection fraction (EF%), [27.9% (1.4) in AMI versus 38.0 (3.1) in AMI-TH (A), P \ 0.05], and favorably remodeled LV chamber while a-MHC was the dominant isoform expres- sed. In AMI-TH (B) mice, TH treatment resulted in increased mortality as compared to untreated mice (73% vs 47%, P \ 0.05), while the favorable effect of TH was not evident in the survived animals. At the molecular level, TH, at the replacement dose, modestly increased p-Akt levels in the myocardium without any change in p-ERK levels. On the contrary, TH at the higher dose resulted in further increase in p-Akt along with an increase in p-ERK levels. In conclusion, TH appears to have a dose-dependent bimodal effect on post-ischemic cardiac performance and this effect may, at least in part, be mediated by a distinct pattern of activation of Akt and ERK signaling. Keywords Thyroid hormone Á Myocardial infarction Á Heart failure Á Cardiac regeneration Á Kinase signaling Introduction Although it has long been recognized that thyroid hormone (TH) levels in plasma drop after acute or chronic illnesses, a phenomenon known as non-thyroidal illness, the physio- logical significance of this response remains largely unknown and there is much controversy as to whether this clinical condition requires treatment [1, 2]. TH levels are decreased after acute myocardial infarction [3, 4], in cardiac operations [5] and in heart failure [6]. This response is now shown to be related to patient’s morbidity and mortality. Thus, patients with myocardial infarction or heart failure and low T3 levels in plasma have high mortality [3, 7], while T3 levels in plasma are shown to be strongly correlated to the recovery of function after myocardial infarction [4] or the maximal oxygen consumption in patients with heart failure [8, 9]. This clinical evidence clearly points out that TH may be critical for the response of the myocardium to stress. Indeed, experimental studies using cell and animal models show that thyroid hormone receptor (TR) signaling is altered after myocardial ischemia or mechanical loading with important physiological consequences, while TH treatment may have beneficial effects [10–25]. Till now, the beneficial effect of TH treatment has not been documented in patients. Thus, over four decades, results from the Coronary Drug Project (CDP) have shown a rather detrimental than benefi- cial effect of TH treatment [26, 27]. Along this line, I. Mourouzis Á P. Mantzouratou Á G. Galanopoulos Á E. Kostakou Á N. Roukounakis Á A. D. Kokkinos Á C. Pantos (&) Department of Pharmacology, University of Athens, 75 Mikras Asias Ave, 11527 Goudi, Athens, Greece e-mail: cpantos@med.uoa.gr D. V. Cokkinos Biomedical Research Foundation, Academy of Athens, Athens, Greece 123 Mol Cell Biochem (2012) 363:235–243 DOI 10.1007/s11010-011-1175-9