Myocardial Infarction Induces Cardiac Fibroblast Transformation within Injured and Noninjured Regions of the Mouse Heart

Heart
failure (HF) is associated with pathological remodeling of
the myocardium, including the initiation of fibrosis and scar formation
by activated cardiac fibroblasts (CFs). Although early CF-dependent
scar formation helps prevent cardiac rupture by maintaining the heart’s
structural integrity, ongoing deposition of the extracellular matrix
in the remote and infarct regions can reduce tissue compliance, impair
cardiac function, and accelerate progression to HF. In our study,
we conducted mass spectrometry (MS) analysis to identify differentially
altered proteins and signaling pathways between CFs isolated from
7 day sham and infarcted murine hearts. Surprisingly, CFs from both
the remote and infarct regions of injured hearts had a wide number
of similarly altered proteins and signaling pathways that were consistent
with fibrosis and activation into pathological myofibroblasts. Specifically,
proteins enriched in CFs isolated from MI hearts were involved in
pathways pertaining to cell–cell and cell–matrix adhesion,
chaperone-mediated protein folding, and collagen fibril organization.
These results, together with principal component analyses, provided
evidence of global CF activation postinjury. Interestingly, however,
direct comparisons between CFs from the remote and infarct regions
of injured hearts identified 15 differentially expressed proteins
between MI remote and MI infarct CFs. Eleven of these proteins (Gpc1, Cthrc1, Vmac, Nexn, Znf185, Sprr1a, Specc1, Emb, Limd2, Pawr, and Mcam) were higher in MI infarct CFs, whereas
four proteins (Gstt1, Gstm1, Tceal3, and Inmt) were higher in MI remote CFs. Collectively, our study
shows that MI injury induced global changes to the CF proteome, with
the magnitude of change reflecting their relative proximity to the
site of injury.