Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes.
Yeast silent information regulator 2 (Sir2), a nicotinamide adenine dinucleotide-dependent histone deacetylase (HDAC) and founding member of the HDAC class III family, functions in a wide array of cellular processes, including gene silencing, longevity, and DNA damage repair. We examined whether or not the mammalian ortholog Sir2 affects growth and death of cardiac myocytes. Cardiac myocytes express Sir2alpha predominantly in the nucleus. Neonatal rat cardiac myocytes were treated with 20 mmol/L nicotinamide (NAM), a Sir2 inhibitor, or 50 nmol/L Trichostatin A (TSA), a class I and II HDAC inhibitor. NAM induced a significant increase in nuclear fragmentation (2.2-fold) and cleaved caspase-3, as did sirtinol, a specific Sir2 inhibitor, and expression of dominant-negative Sir2alpha. TSA also modestly increased cell death (1.5-fold) but without accompanying caspase-3 activation. Although TSA induced a 1.5-fold increase in cardiac myocyte size and protein content, NAM reduced both. In addition, NAM caused acetylation and increases in the transcriptional activity of p53, whereas TSA did not. NAM-induced cardiac myocyte apoptosis was inhibited in the presence of dominant-negative p53, suggesting that Sir2alpha inhibition causes apoptosis through p53. Overexpression of Sir2alpha protected cardiac myocytes from apoptosis in response to serum starvation and significantly increased the size of cardiac myocytes. Furthermore, Sir2 expression was increased significantly in hearts from dogs with heart failure induced by rapid pacing superimposed on stable, severe hypertrophy. These results suggest that endogenous Sir2alpha plays an essential role in mediating cell survival, whereas Sir2alpha overexpression protects myocytes from apoptosis and causes modest hypertrophy. In contrast, inhibition of endogenous class I and II HDACs primarily causes cardiac myocyte hypertrophy and also induces modest cell death. An increase in Sir2 expression during heart failure suggests that Sir2 may play a cardioprotective role in pathologic hearts in vivo.
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA.
Ralph R
RR
Alcendor
Lorrie A
LA
Kirshenbaum
Shin-ichiro
S
Imai
Stephen F
SF
Vatner
Junichi
J
Sadoshima
D000107:Acetylation / Q000187:drug effects; D000470:Alkaloids; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D053119:Benzophenanthridines; D002467:Cell Nucleus / Q000201:enzymology; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004285:Dogs; D020868:Gene Silencing / Q000502:physiology*; D005799:Genes, Dominant; D016158:Genes, p53; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology*; D006352:Heart Ventricles / Q000166:cytology; D006877:Hydroxamic Acids / Q000494:pharmacology; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000473:pathology*; D008136:Longevity / Q000235:genetics*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009284:Naphthols / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000470:Alkaloids; D001549:Benzamides; D053119:Benzophenanthridines; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; D006877:Hydroxamic Acids; D009284:Naphthols; D010617:Phenanthridines; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C439060:sirtinol; D009536:Niacinamide; C012589:trichostatin A; D009320:Atrial Natriuretic Factor; C016299:chelerythrine; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins