Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism

Endin Nokik Stujanna, Endin (2018) Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism. Doctoral thesis, University Of Tsukuba.

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As a leading cause of death and an increasing health burden worldwide,
myocardial infarction (MI) remains one of the most important clinical
entities. After the onset of MI, the left ventricle (LV) undergoes a
continuum of molecular, cellular, and extracellular responses that result in
LV wall thinning, dilatation, and dysfunction (Thygesen et al., 2012). The
cardiac healing and remodeling process after MI can be divided into four
phases: the death of cardiomyocytes, acute inflammation, the formation of
granulation tissue, and scar formation (Figure 1). Acute inflammation
usually occurs just after the onset of myocardial infarction. During this
phase, neutrophils and monocytes are recruited into necrotic tissue, and
they release inflammatory cytokines and matrix metalloproteinase (MMP)
(Liehn et al., 2011). Inflammatory cell infiltration and MMP production
play important roles in the degradation of necrotic debris and the
subsequent scar formation. However, excess inflammatory response and
MMP overproduction are likely to induce adverse cardiac remodeling,

leading to left ventricular dilatation, dysfunction, and cardiac rupture
(Frangogiannis, 2015; Matsui et al., 2010). Despite the significant progress
made on therapeutic strategies for MI in last few decades, mortality and
morbidity remain high, and adverse cardiac remodeling after MI remains a
critical issue to be solved. Therefore, continuous improvement in
medications for the disease is still a major concern in global medical
Nuclear receptors (NRs) are members of a large superfamily and
widely considered as ligand-activated transcriptional factors. These were
originally found within cells that are responsible for sensing steroid and
thyroid hormones and certain other molecules, and work with other
proteins to regulate the expression of specific genes, thereby controlling the
development, homeostasis, and metabolism of the organism (Chambon,
2005; Evans, 2005). Nuclear receptors represent one of the most important
targets for therapeutic drug development, and many compounds targeted
for nuclear receptors have already been developed as marketable drugs, e.g.
peroxisome proliferator-activated receptor α and γ activators.
Rev-erb belongs to a nuclear receptor superfamily, and contains two
subgroups, Rev-erb α (NR1D1) and β (NR1D2). Rev-erb α is highly
expressed in the liver, skeletal muscle, adipose tissue, heart and brain,

participating in the development and circadian regulation of these tissues.
(Solt et al., 2012). Rev-erb β displays a similar structure and has been
implicated in the control of lipid and glucose metabolism and circadian
rhythm, collaborating extensively with Rev-erb α (Bugge et al., 2012).
Heme was identified as a physiological ligand for Rev-erb receptor, which
regulates their transcriptional activity (Figure 2). Moreover, Rev-erb α
displays a hydrophobic interface that binds the corepressor N-CoR, making
it a potent transcriptional repressor (Solt et al., 2012; Woldt et al., 2013).
Previous studies reported Rev-erb α regulated mitochondrial biogenesis in
loss- and gain-of-function settings. Rev-erb α deficiency in skeletal muscle
resulted in reduced mitochondrial content and ATP production through
deactivating AMPK-SIRT1–PGC1 signaling pathway (Woldt et al., 2103).
Recently, SR9009 and SR9011 were developed as synthetic Rev-erb
agonists, which facilitates Rev-erb α to recruit its corepressor NCoR and
repress downstream targets (Solt et al., 2012). From the results of the
previous studies using agonists, it has been identified that the nuclear
receptor Rev-erb α plays a pivotal role in the modulation of skeletal muscle
oxidative capacity by regulating mitochondrial biogenesis and autophagy,
leading to increasing in exercise capacity (Woldt et al., 2013). Moreover,
long-term treatment with SR9009 was shown to reduce atherosclerotic

plaque by decreasing the ratio of proinflammatory M1 macrophages to
anti-inflammatory M2 macrophages in low-density lipoprotein (LDL)
receptor-deficient mice fed a Western diet (Sitaula et al., 2015). Therefore,
Rev-erb is expected to be a promising therapeutic target for metabolic
syndrome and atherosclerotic disease. However, little is known about the
Rev-erb agonist effect on the progression of MI and heart failure

Item Type: Thesis (Doctoral)
Subjects: R Medicine
Depositing User: Endin Nokik Stujanna
Date Deposited: 08 Dec 2022 23:29
Last Modified: 08 Dec 2022 23:29

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