The role of sirtuins in cardiac disease

Abstract

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.

Keywords: FoxO; cell death/survival; longevity; sirtuin-activating compounds.

Fig. 1.

Signaling pathways of silent mating-type information regulation (Sirt) 1 in the heart. Sirt1 can modulate fatty acid oxidation, cardiac hypertrophy, apoptosis, oxidative stress, and autophagy through deacetylation of NF-κB, Akt, Forkhead box class O (FoxO), and p53. PPAR-α, peroxisome proliferator-activated receptor-α; Trx1, thioredoxin-1; Bcl-xL, B-cell lymphoma-extra large.

Fig. 2.

Signaling pathways of Sirt3 in the heart. Sirt3 regulates Mitochondrial permeability transition pore (mPTP) opening, apoptosis, and cell survival, mainly through deacetylation of mitochondrial proteins, including cyclophilin D (CypD), Ku70, and complex I, independently of transcription. Sirt3 also deacetylates FoxO, leading to transcriptional upregulation of MnSOD and catalase and inhibition of cardiac hypertrophy.

Fig. 3.

Signaling pathways of Sirt6 in the heart. Sirt6 deacetylates histones at Lys9, thereby suppressing the insulin-like growth factor (IGF)-Akt pathway and cardiac hypertrophy. Sirt6 increases the resistance to hypoxic injury in the heart by stimulating AMPK-α and Bcl2 and inhibiting NK-κB and Akt. pAkt, phospho-Akt; Ac, acetylated.