Quantitative Proteomics and Immunohistochemistry Reveal Insights into Cellular and Molecular Processes in the Infarct Border Zone One Month after Myocardial Infarction

Postinfarction
remodeling and expansion of the peri-infarct border
zone (BZ) directly correlate with mortality following myocardial infarction
(MI); however, the cellular and molecular mechanisms underlying remodeling
processes in the BZ remain unclear. Herein, we utilized a label-free
quantitative proteomics approach in combination with immunohistochemical
analyses to gain a better understanding of processes contributing
to postinfarction remodeling of the peri-infarct BZ in a swine model
of MI with reperfusion. Our analysis uncovered a significant down-regulation
of proteins involved in energy metabolism, indicating impaired myocardial
energetics and possibly mitochondrial dysfunction, in the peri-scar
BZ. An increase in endothelial and vascular smooth muscles cells,
as well as up-regulation of proteins implicated in vascular endothelial
growth factor (VEGF) signaling and marked changes in the expression
of extracellular matrix and subendothelial basement membrane proteins,
is indicative of active angiogenesis in the infarct BZ. A pronounced
increase in macrophages in the peri-infarct BZ was also observed,
and proteomic analysis uncovered evidence of persistent inflammation
in this tissue. Additional evidence suggested an increase in cellular
proliferation that, concomitant with increased nestin expression,
indicates potential turnover of endogenous stem cells in the BZ. A
marked up-regulation of pro-apoptotic proteins, as well as the down-regulation
of proteins important for adaptation to mechanical, metabolic, and
oxidative stress, likely contributes to increased apoptosis in the
peri-infarct BZ. The cellular processes and molecular pathways identified
herein may have clinical utility for therapeutic intervention aimed
at limiting remodeling and expansion of the BZ myocardium and preventing
the development of heart failure post-MI.