Intravenous Administration Of Stembells in The Acute Phase After Myocardial Infarction Reduces The Pro-Inflammatory Status Of The Intramyocardial Vasculature in A Rat Model
Background: Acute myocardial infarction (AMI) induces a pro-inflammatory status of the intramyocardial vasculature in which N?-(carboxymethyl)lysine (CML), an advanced glycation end product, and NOX2, a source of reactive oxygen species (ROS), play an important role. As such they form attractive therapeutic targets to prevent future heart failure development. Previously, we found that adipose tissue derived stem cells coupled to antibody-targeted microbubbles (the so-called StemBells (StB)) improved cardiac function when administered intravenously, also when applied early after AMI in a rat model. Its effect on the intramyocardial microvasculature however is unknown. In the present study we have analyzed its effect on both CML and NOX2 depositions in the intramyocardial vasculature in a rat AMI model.
Methods: AMI was induced by ligation of the left coronary artery followed by reperfusion in male Wistar rats. In a subset of these rats, intravenous StB were administered at day 1 [n=8] (group StB day 1), day 7 [n= 7] (group StB 7) or days 1 and 7 [n=7] (group StB day 1+7) post-AMI. Animals were sacrificed at day 42 post-AMI. The effect on CML (immunohistochemical score and/or the number of blood vessels with different intensity scores) and NOX2 positivity (the number of positive blood vessels) was then analyzed using immunohistochemistry.
Results: AMI induced a significant increase in both CML (from 0.08 ± 0.01 /mm2 in controls up to 0.3 ± 0.05/mm2 in the AMI group) and NOX2 positivity of the intramyocardial vasculature (from 0.1 ± 0.01 in non-infarcted control rats to 0.53 ± 0.08 in AMI rats). StB therapy significantly decreased NOX2 (0.11 ± 0.02 treated on day 1 post-AMI, 0.19 ± 0.02 when treated on day 7 post-AMI and 0.25 ± 0.04 with administration at day 1 and day 7 post-AMI), without significant differences between the three StB groups) and CML positivity (immunohistochemical score: 0.13 ± 0.03 when treated at day 1 post-AMI, 0.17 ± 0.02 when treated on day 7 post-AMI and 0.13 ± 0.01 with treatment on day 1 and day 7 post-AMI) of the intramyocardial vasculature in all three groups. A significant decreasing effect of StB therapy on the lowest CML intensity (score 1) was found in all three StB groups, on the intermediate (score 2) in the StB day 7 and StB day 1+7 group, and finally on the highest CML intensity (score 3) in the StB day 1+7 group only.
Conclusion: StB therapy reduced the pro-inflammatory status of the intramyocardial vasculature post- AMI when applied in the acute phase post-AMI.