@phdthesis{repository17280,
            year = {2018},
          school = {University Of Tsukuba},
           title = {Rev-erb agonist improves adverse cardiac 
remodeling and survival in myocardial 
infarction through an anti-inflammatory 
mechanism},
        abstract = {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 
research.
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 {\ensuremath{\alpha}} and {\ensuremath{\gamma}} activators. 
Rev-erb belongs to a nuclear receptor superfamily, and contains two 
subgroups, Rev-erb {\ensuremath{\alpha}} (NR1D1) and {\ensuremath{\beta}} (NR1D2). Rev-erb {\ensuremath{\alpha}} 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 {\ensuremath{\beta}} displays a similar structure and has been 
implicated in the control of lipid and glucose metabolism and circadian 
rhythm, collaborating extensively with Rev-erb {\ensuremath{\alpha}} (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 {\ensuremath{\alpha}} 
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 {\ensuremath{\alpha}} regulated mitochondrial biogenesis in 
loss- and gain-of-function settings. Rev-erb {\ensuremath{\alpha}} 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 {\ensuremath{\alpha}} 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 {\ensuremath{\alpha}} 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},
          author = {Endin Nokik Stujanna, Endin},
             url = {http://repository.uhamka.ac.id/id/eprint/17280/}
}