Ivabradine-Stimulated Microvesicle Release Induces Cardiac Protection against Acute Myocardial Infarction.
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2020
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International Journal of Molecular Sciences
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Abstract
Ivabradine can reduce heart rate through inhibition of the current I(f ) by still unexplored
mechanisms. In a porcine model of ischemia reperfusion (IR), we found that treatment with 0.3 mg/kg
Ivabradine increased plasma release of microvesicles (MVs) over Placebo, as detected by flow
cytometry of plasma isolated from pigs 7 days after IR, in which a tenfold increase of Extracellular
Matrix Metalloproteinase Inducer (EMMPRIN) containing (both high and low-glycosylated) MVs,
was detected in response to Ivabradine. The source of MVs was investigated, finding a 37% decrease
of CD31+ endothelial cell derived MVs, while CD41+ platelet MVs remained unchanged. By contrast,
Ivabradine induced the release of HCN4+ (mostly cardiac) MVs. While no differences respect to
EMMPRIN as a cargo component were found in endothelial and platelet derived MVs, Ivabradine
induced a significant release of EMMPRIN+/HCN4+ MVs by day 7 after IR. To test the role of
EMMPRIN+ cardiacMVs (EMCMV), H9c2 cellmonolayers were incubated for 24 h with 107 EMCMVs,
reducing apoptosis, and increasing 2 times cell proliferation and 1.5 times cell migration. The in vivo
contribution of Ivabradine-induced plasma MVs was also tested, in which 108 MVs isolated from
the plasma of pigs treated with Ivabradine or Placebo 7 days after IR, were injected in pigs under IR,
finding a significant cardiac protection by increasing left ventricle ejection fraction and a significant
reduction of the necrotic area. In conclusion ivabradine induces cardiac protection by increasing at
least the release of EMMPRIN containing cardiac microvesicles.
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Keywords
Acute myocardial infarction, Ischemia reperfusion, Microvesicles, Ivabradine, EMMPRIN