Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction

Abstract

Background: Bone Marrow (BM) progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I) are effective in reducing mortality and preventing left ventricular (LV) function deterioration after myocardial infarction.

Methods: We investigated the short term effects of BM mononuclear cells (BMMNCs) therapy on the pro-inflammatory cytokines (pro-CKs) and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage. Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12), pharmacological therapy (ACE-I; n = 14, receiving quinapril), and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion). Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL)1beta, IL-6, tumor necrosis factor (TNF)alpha was performed (multiplex proteome arrays) on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference.

Results: Concerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFalpha inversely correlated with LV fractional shortening.

Conclusion: After myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats.

Figure 1

Design of the experiment.

Figure 2

Top panels. Representative original chemiluminescent images obtained from the studied rats. The loading scheme of the cytokines is shown on the first top left image. Bottom panels. Surface plots obtained from the corresponding chemiluminescent images showing on the z axis the relative intensity of the responce; the luminance of the image is interpreted as height of the plot. In the AMI plot (untreated rat) is clearly evident the pro-Cks increase if compared with the ACE-I and Stem plot where, on the contrary, the anti-inflammatory Cks are prevalent. Plots are obtained by using Interactive 3D surface plot v2.1 by K. Barthel a specific software developed for ImageJ v1.37, a freeware image analysis package developed by W. Rasband. AMI: acute myocardial infarction.

Figure 3

Top panels. Original M-mode echocardiographic tracings showing left ventricular end diastolic diameters (LVEDd), respectively in an Untreated (left), an ACE-I (centre) and a BMMNCs (right) treated rat. Bottom panels. In the same rats, immunohistochemistry images showing TNFα positive elements (DAB+) and the corresponding TNFα.serum levels.