261
3 Molecular Biology of Cardiac Remodelling and Fibrosis
Fibroblasts represent an essential and dynamic cell population in the heart in that
they play critical roles in both physiology (development) and pathology (injury). A
broad range of molecular signal cascades regulate/modulate the triggering, progres-
sion and regression of the fibrotic response. The complexity of the interactions
between these signaling cascades greatly complicate the elucidation and understand-
ing of fibrosis at the molecular level, especially given that the relative significance of
each pathway varies according to the underlying cause of the fibrotic reaction [ 25 ].
The innate and adaptive immune responses of white blood cells and mast cells, along
with hormones and growth factors, as well as para/ autocrine (myo)fibroblast and
cardiomyocytes signaling all contribute to the intrinsic cellular changes in myocar-
dium. These changes can sustain fibrosis by differentiating, recruiting, activating
and stimulating the proliferation of the extracellular matrix–producing myofibro-
blasts. Differentiating between myofibroblasts and fibroblasts is key to the develop-
ment of effective therapeutic interventions. Cardiac myofibroblasts were first
described in the literature in the 1970s [ 20 ]. Distinguishing features of these cells
include expanded cytoplasm, microfilament bundles, serrated nuclei and highly
defined Golgi complex and endoplasmic reticulum [ 21 , 22 ]. Recent studies have
further contributed by identifying transcription factors associated with various func-
tions of activated cardiac fibroblasts. Two such proteins are sclerosis and myocardin-
related transcription factors. Scleraxis plays a role downstream of transforming
growth factor beta (TGFβ) and is involved in the synthesis of the extracellular matrix.
Myocardin-related transcription factors initiate changes in the cytoskeleton and also
upregulate expression of alpha-smooth muscle actin (αSMA) during fibroblast acti-
vation [ 19 , 23 ]. In response to stress signals, the stimulation of gene expression
associated with fibrosis requires the intervention of sequence- specific DNA-binding
transcription factors. These factors include the transforming growth factor beta sig-
naling proteins SMAD2/ SMAD3, nuclear factor of activated T cells (NFAT), myo-
cardin-related transcription factors (MRTF) and serum response factor (SRF) [ 29 ].
To date, the strongest signature discovered in cardiac fibroblasts are the transcription
factors the T-box transcription factor Tbx20 and the zinc finger transcription factor
Gata4, as opposed to the heterogeneous expression found for the epicardial markers
such as Wilms’ tumor-1 (Wt1) and epicardin (or transcription factor 21, Tcf21).
Other cardiac fibroblasts transcription factors that are shared with both cardiomyo-
cytes and cardiac progenitor cells include members of the T-box family (Tbx2, Tbx5
and Tbx20), members of the GATA family (Gata4, Gata4, Gata6) the muscle marker
Myocyte-specific enhancer factor 2C (Mef2c), and the more heart-specific marker
Heart and neural crest derivatives-expressed protein-2 (Hand2) [ 24 ]. The consider-
able overlap of gene expression signatures that are shared between cardiac fibro-
blasts and cardiomyocytes (Table 14.2) are highly suggestive that both cell types
could share similar pathways in fibrotic processes and/or that the cardiac fibroblasts
could naturally be reprogrammed into cardiomyocytes, were it not for the likely
presence of strong endogenous repressors of such transdifferentiation [ 28 ].
14 Cardiac Fibrosis: The Beneficial Effects of Exercise in Cardiac Fibrosis