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2015 ; 309
(9
): H1375-89
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The role of sirtuins in cardiac disease
#MMPMID26232232
Matsushima S
; Sadoshima J
Am J Physiol Heart Circ Physiol
2015[Nov]; 309
(9
): H1375-89
PMID26232232
show ga
Modification of histones is one of the important mechanisms of epigenetics, in
which genetic control is determined by factors other than an individual's DNA
sequence. Sirtuin family proteins, which are class III histone deacetylases, were
originally identified as gene silencers that affect the mating type of yeast,
leading to the name "silent mating-type information regulation 2" (SIR2). They
are characterized by their requirement of nicotinamide adenine dinucleotide for
their enzyme activity, unlike other classes of histone deacetylases. Sirtuins
have been traditionally linked to longevity and the beneficial effects of calorie
restriction and DNA damage repair. Recently, sirtuins have been shown to be
involved in a wide range of physiological and pathological processes, including
aging, energy responses to low calorie availability, and stress resistance, as
well as apoptosis and inflammation. Sirtuins can also regulate mitochondrial
biogenesis and circadian clocks. Seven sirtuin family proteins (Sirt1-7) have
been identified as mammalian SIR2 orthologs, localized in different subcellular
compartments, namely, the cytoplasm (Sirt1, 2), the mitochondria (Sirt3, 4, 5),
and the nucleus (Sirt1, 2, 6, 7). Sirt1 is evolutionarily close to yeast SIR2 and
has been the most intensively investigated in the cardiovascular system.
Endogenous Sirt1 plays a pivotal role in mediating the cell death/survival
process and has been implicated in the pathogenesis of cardiovascular disease.
Downregulation of Sirt2 is protective against ischemic-reperfusion injury.
Increased Sirt3 expression has been shown to correlate with longevity in humans.
In addition, Sirt3 protects cardiomyocytes from aging and oxidative stress and
suppresses cardiac hypertrophy. Sirt6 has also recently been demonstrated to
attenuate cardiac hypertrophy, and Sirt7 is known to regulate apoptosis and
stress responses in the heart. On the other hand, the roles of Sirt4 and Sirt5 in
the heart remain largely uncharacterized.
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