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  • In human samples Haywood et al showed that

    2020-07-27

    In human samples, Haywood et al. [20] showed that iNOS was undetectable in control heart samples but could be detected in 36 of 51 patients with heart failure. Our data show that iNOS love herself in the left ventricle is increased after MI and can be attenuated by treatment with AAV9-EP4, consistent with a cardioprotective effect. iNOS is also one marker for the M1 macrophage phenotype but it is unclear from our data obtained from left ventricle samples whether the iNOS originates from resident/infiltrating macrophages or another cell type such as cardiomyocytes. If the former, then the reduction noted in iNOS may relate simply to a reduction in the number of infiltrating macrophages observed after AAV9-EP4 treatment. Alternatively, PGE2 has been shown to have anti-inflammatory effects in macrophages by reducing TNFα expression and increasing Interleukin 10 expression via the EP4/cAMP/protein kinase A (PKA) pathway, which promotes macrophage M2 polarization [[21], [22], [23]]. It remains to be elucidated however, if overexpression of EP4 in the left ventricle mediates macrophage polarization towards an anti-inflammatory M2 phenotype and our data using a limited number of markers does not allow us to draw any conclusions. Another aspect of cardiac remodeling involves the matrix metalloproteinases (MMPs) family of proteins and other molecules that play a role in collagen deposition. Specifically, MMP-2 has been implicated in LV remodeling and furthermore, MMP-2 KO mice are reported to have lower incidences of cardiac rupture after MI [24,25], although the mechanism of how MMP-2 contributes to cardiac rupture is not well understood. Also, reports show that broad inhibition of MMPs contributes to attenuation of LV dilatation [26,27]. Several MMPs are involved in this process, although MMP-2 may play a key role. Matsumura et al. [13] reported that targeted deletion of MMP-2 in mice profoundly improved survival rates after MI. Moreover, they reported that deletion of MMP-2 completely reduced macrophage migration after MI. Our data using in situ zymography which measures gelatinase activity (MMP-2 and MMP-9) is interesting but rather perplexing in that we observe increased MMP activity in sham-operated animals treated with AAV9-EP4 that is not significantly increased further after MI. Overall, our data indicates that treatment with AAV9-EP4 alters the cardiac remodeling process after MI and changes in MMP activity may be an important player in the mechanism of reduced macrophage migration and the subsequent prevention of LV dilatation we observed with overexpression of EP4. The secreted protein, acidic and rich in cysteines (SPARC) was also shown to affect remodeling after MI. Schellings et al. [28] reported that deletion of SPARC increased rupture following MI and a role for this molecule in macrophage clearance has also been postulated [29]. Our data shows no effect of EP4 overexpression on this molecule, consistent with its high expression in fibroblasts and endothelial cells but low expression in myocytes [30].