Stembell Therapy Reduces Macrophages in Atherosclerotic Aortic Valves after Myocardial Infarction

Abstract

Background: Previously, we have shown that StemBell therapy (i.e. mesenchymal stem cell-microbubble complexes subjected to ultrasound) reduced plaque inflammation and plaque destabilization in the aortic root, and thereby inhibited atherosclerosis exacerbation after myocardial infarction (MI). MI also has an effect on heart valves as it increases valve thickness and remodeling. Moreover, hemodynamic disturbances following MI have also been suggested to affect aortic valve (AV) pathology. Therefore, we have analyzed StemBell therapy on AV after MI. Methods: In atherosclerotic Apolipoprotein E-deficient mice that were fed a high-fat Western diet, MI was induced via permanent left coronary artery ligation. Six days postMI, the mice received either 5 × 105/100 μL StemBells or vehicle intravenously. The effects of StemBell treatment on the AV were determined 28 days post-MI via (immuno)histochemical analyses. Results: In all mice, we observed morphological signs of AV sclerosis including thickened valve leaflets, acellularity, glycosaminoglycan (GAG) transformation and fibrosis, but without evidence of mineralization, suggestive for more early-stage AV disease in our mouse model. StemBell therapy resulted in a significantly decreased infiltration of Mac3+ macrophages in the AV, without significantly affecting CD163+ macrophages, CD45+ leukocytes and monocytic chemoattractants. The advanced glycation end products (AGEs) Nε-(carboxymethyl) lysine (CML) and methylglyoxal (MGO) were decreased in the AV of StemBell-treated mice, albeit not significantly. No significant effects were observed in AV thickness, fibrosis, GAGs, lipidand calcium-deposits. StemBell therapy did however increase AV iron deposits, although not significant. Conclusion: StemBell therapy reduced macrophage infiltration of AV after MI without changing valve morphology.