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. 2016 May 3:7:115.
doi: 10.3389/fphar.2016.00115. eCollection 2016.

Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs

Christoffer K-J Stark  1 , Miikka Tarkia  2 , Rasmus Kentala  3 , Markus Malmberg  4 , Tommi Vähäsilta  1 , Matti Savo  3 , Ville-Veikko Hynninen  5 , Mikko Helenius  6 , Saku Ruohonen  3 , Juho Jalkanen  7 , Pekka Taimen  8 , Tero-Pekka Alastalo  6 , Antti Saraste  2 , Juhani Knuuti  2 , Timo Savunen  3 , Juha Koskenvuo  3
Affiliations

Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs

Christoffer K-J Stark et al. Front Pharmacol. .

Abstract

The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.

Keywords: cardioprotection; cardiopulmonary bypass; coagulation; ischemia-reperfusion injury; thymosin beta 4; vasoconstriction.

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Figures

FIGURE 1
FIGURE 1
Individual serum concentrations of thymosin beta 4 and mean concentrations in two control (dotted line) and two treated animals (black line). Thymosin beta 4 was administered intravenously (6 mg/kg) at 0 min and at 360 min (arrowheads). Bar indicates ischemic period.
FIGURE 2
FIGURE 2
The contractile effects of TB4 on small mesentery arteries (A) and the effects of TB4 on coronary relaxation with TB4 alone and with nitric oxide synthase inhibitor, L-NNA (B) on arteries from four animals (mean ± SEM).
FIGURE 3
FIGURE 3
Maximum blood clot firmness in blood samples from three animals treated with different concentrations of TB4. EXTEM measures activity of the extrinsic and INTEM of the intrinsic pathway. FIBTEM is used for the assessment of fibrinogen status in the absence of platelets (individual values + mean).
FIGURE 4
FIGURE 4
Percentage of TUNEL-positive cells (A) in left and right ventricle tissue samples (n = 3 + 4) 30 h post-reperfusion and plasma concentrations of cTnT (B) 6 and 24 h post-reperfusion (n = 4 + 4; individual values + mean).
FIGURE 5
FIGURE 5
Global myocardial blood flow (A) and coronary flow reserve (B) assessed with cardiac [15O]H2O positron emission tomography 25 h post-reperfusion (n = 4 + 4). Correlation between myocardial blood flow at rest and cTnT in plasma samples (C) (individual values + mean).
FIGURE 6
FIGURE 6
LVEF (A), LVEDV (B), and LVESV (C) assessed by cardiac magnetic resonance imaging 28 h post-reperfusion (n = 4 + 4; individual values + mean).
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