Dose-dependent effects of thyroid hormone on post-ischemic cardiac performance: potential involvement of Akt and ERK signalings

Abstract

The present study explored the effects of thyroid hormone (TH) treatment on post-ischemic cardiac function and potential implicated mechanisms. Acute myocardial infarction (AMI) was induced in mice by coronary 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 α-MHC was the dominant isoform expressed. 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.

MuRF1 mono-ubiquitinates TRα to inhibit T3-induced cardiac hypertrophy in vivo

“…TH induces molecular changes that benefit the failing heart, including the stimulation of pro-survival pathways such as Akt and mTOR (Mourouzis et al 2012) that is accompanied by improved cardiac function, paralleling changes induced by exercise, mediated by IGF-1 (Ojamaa 2010), to drive increases in contractile proteins critical to cardiac function and performance (Periasamy et al 2008). Exercise has also been shown to increase myocardial TR expression and T3 levels in a small cohort of HF patients with ventricular assist devices (Adamopoulos et al 2013), underscoring the role for TH in promoting positive adaptive remodeling of the injured heart.…”

Increased Procurement of Thoracic Donor Organs After Thyroid Hormone Therapy

“…The mechanism has been previously discussed, 20,21 and there have subsequently been several reports of their value in other "low-T 3 " conditions (euthyroid sick syndrome). [21][22][23][24][25][26][27] Hormonal therapy that included T 3 was first administered to a series of human braindead potential organ donors at Groote Schuur Hospital in 1984. 28 The initial regimen involved the hourly administration of T 3 (2μg), cortisol (100mg), and insulin (20units).…”

“…We did not differentiate between therapy with T 3 vs T 4 , but there is some experimental and clinical evidence that T 3 may be preferable to T 4 . [22][23][24][25][26][27] If all treateddonors had received T 3 , therefore, it is possible the results of heart and lung procurement would have been even better.…”

Thyroid Hormones and the Heart; a Paradigm of Exquisite Fine Tuning, Combining Ancient Hellenic and Oriental Wisdom

“…In animals we have shown that dosage is important: Greater doses of T3 after old infarcts were beneficial [37] however in early postinfarct rats they actually caused greater REM and CHF, associated with an overt increase of Akt, as already mentioned [22]. Ojamaa et al [38] in rats found that only higher doses (20 mg/day) increased SERCA-2α and SERCA-2α/PLB ratio and αMHC.…”

“…The "nothing in excess" adage is very pertinently pictured by our finding [22] that Akt, a determining factor for the expression of psychological H, becomes deleterious when overexpressed due to high T3 doses . Accordingly, Matsui et al [23], have also shown that transgenic rats overexpressing Akt develop myocardial fibrosis.…”