Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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Gene expression often requires the participation of specific transcription factors.

Transcription factors are a wide variety of proteins that either stimulate or suppress

the transcription of genomic DNA into messenger RNA (mRNA). MicroRNAs

(miRNA) are small non coding RNA molecules that are of great importance in the

regulation of gene expression. The important roles played by miRNAs in the patho-

logical process of cardiac diseases have recently been elucidated and represent one

of the most rapidly growing areas of research in cellular and molecular medicine

[ 35 , 36 ]. A growing body of research findings are suggesting that miRNAs regulate

many processes observed in the development of cardiac fibrosis such as prolifera-

tion, cell death or changes in metabolism, structure, and function. It appears that

multiple miRNAs (e.g. the muscle-specific miRNAs miR-1, miR-133 and miR-208,

as well as other miRNAs including miR-18b, miR-21 and miR-195) play a role in

cardiac fibrosis and that each one of them can determine pathological processes in

an independent fashion [ 36 , 37 ].

On the other hand, recent studies have also clearly suggested a pivotal role for the

epigenetic control of gene expression in the pathogenesis of cardiac fibrosis although

major knowledge gaps still exist. Epigenetics is a type of gene regulation that results

in changes being imparted to DNA or proteins in nucleosomes, without modifica-

tions to the underlying sequence of nucleotides. A number of post-translational mod-

ification can target histone tails. These modifications can have drastic effects on the

expression of genes and are central to the processes of epigenetic control [ 30 – 33 ].

The possibility of epigenetic involvement in the regulation of cardiac fibrosis  -

through histone deacetylases (HDACs), histone acetyltransferases (HATs), acetyl-

Table 14.2 Cardiogenic signature of transcription factors expressed in fibroblasts, cardiac
progenitor cells and adult cardiomyocytes

Type of cardiac cells Transcription factors Overlap in cellular expression

Fibroblasts Tbx2/5/20; Nkx2–5; Hand2;

Gata4/5/6; Mef2c; Wt1; Tbx18

With cardiac progenitor cells and

cardiomyocytes

Tcf21 With cardiac progenitor cells only

Lbh With cardiomyocytes only

Heyl No overlap

Cardiac progenitor cells Tbx2/5/20; Nkx2–5; Hand2;

Gata4/5/6; Mef2c; Wt1; Tbx18

With fibroblasts and

cardiomyocytes

Tcf21 With fibroblasts only

Hand1; Mesp1; Isl1; Tead1;

Mef2a

With cardiomyocytes only

Oct4; Nanog No overlap

Adult cardiomyocytes Tbx2/5/20; Nkx2–5; Hand2;

Gata4/5/6; Mef2c; Wt1; Tbx18

With fibroblasts and cardiac

progenitor cells

Hand1; Mesp1; Isl1; Tead1;

Mef2a;

With cardiac progenitor cells only

Lbh With fibroblasts only

Tbx1/3; Srf; Elk1/3/4; Foxh1 No overlap

Adapted from Ref. [ 24 ]

J. Kyselovič and J.J. Leddy