EMMPRIN-Targeted Magnetic Nanoparticles for In Vivo Visualization and Regression of Acute Myocardial Infarction.
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2016
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Theranostics, Vol. 6, Nº 4
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Abstract
Inhibition of extracellular matrix (ECM) degradation may represent a mechanism for cardiac
protection against ischemia. Extracellular matrix metalloproteinase inducer (EMMPRIN) is highly
expressed in response to acute myocardial infarction (AMI), and induces activation of several
matrix metalloproteinases (MMPs), including gelatinases MMP-2 and MMP-9. We targeted
EMMPRIN with paramagnetic/fluorescent micellar nanoparticles conjugated with the EMMPRIN
binding peptide AP-9 (NAP9), or an AP-9 scrambled peptide as a negative control (NAPSC). We
found that NAP9 binds to endogenous EMMPRIN in cultured HL1 myocytes and in mouse hearts
subjected to ischemia/reperfusion (IR). Injection of NAP9 at the time of or one day after IR, was
enough to reduce progression of myocardial cell death when compared to Control and NAPSC
injected mice (infarct size in NAP9 injected mice: 32%±6.59 vs Control: 46%±9.04 or NAPSC
injected mice: 48%±7.64). In the same way, cardiac parameters were recovered to almost healthy
levels (LVEF NAP9 63% ± 7.24 vs Control 42% ± 4.74 or NAPSC 39% ± 6.44), whereas ECM
degradation was also reduced as shown by inhibition of MMP-2 and MMP-9 activation. Cardiac
magnetic resonance (CMR) scans have shown a signal enhancement in the left ventricle of NAP9
injected mice with respect to non-injected, and to mice injected with NAPSC. A positive correlation
between CMR enhancement and Evans-Blue/TTC staining of infarct size was calculated
(R:0.65). Taken together, these results point to EMMPRIN targeted nanoparticles as a new approach
to the mitigation of ischemic/reperfusion injury.
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Keywords
Ischemia, Reperfusion, Matrix metalloproteinases, Nanoparticles, EMMPRIN