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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 1, 2009
Contents
Nicotinamide Adenine Dinucleotide
Biology and Disease
Executive Editor: W. Todd Penberthy
Editorial: Pp. 1-2
Niacin Status, NAD Distribution and ADP-Ribose Metabolism
Pp. 3-11
J.B. Kirkland
[Abstract] [Full
text article] [PMID:
19149597 PubMed - indexed for MEDLINE]
Roles of NAD+
/ NADH and NADP+ / NADPH
in Cell Death Pp. 12-19
W. Xia, Z. Wang, Q. Wang, J. Han, C. Zhao,
Y. Hong, L. Zeng, L. Tang and W. Ying
[Abstract] [Full
text article] [PMID:
19149598 PubMed - indexed for MEDLINE]
Nicotinamide Phosphoribosyltransferase
(Nampt): A Link Between NAD Biology, Metabolism, and Diseases
Pp. 20-28
S.-i. Imai
[Abstract] [Full
text article] [PMID:
19149599 PubMed - indexed for MEDLINE]
NAD in Skin: Therapeutic Approaches for
Niacin Pp. 29-38
C.A. Benavente, M.K. Jacobson and
E.L. Jacobson
[Abstract] [Full
text article] [PMID:
19149600 PubMed - indexed for MEDLINE]
Cellular Regulation of SIRT1 Pp.
39-44
J. Milner
[Abstract] [Full
text article] [PMID:
19149601 PubMed - indexed for MEDLINE]
Pharmaceutical Strategies for Activating
Sirtuins Pp. 45-56
A.A. Sauve
[Abstract] [Full
text article] [PMID:
19149602 PubMed - indexed for MEDLINE]
CD38 as a Regulator of Cellular NAD:
A Novel Potential Pharmacological Target for Metabolic Conditions
Pp. 57-63
E.N. Chini
[Abstract] [Full
text article] [PMID:
19149603 PubMed - indexed for MEDLINE]
The Importance of NAD in Multiple Sclerosis
Pp. 64-99
W.T. Penberthy and I. Tsunoda
[Abstract] [Full
text article] [PMID:
19149604 PubMed - indexed for MEDLINE]
The Evolution of Schizophrenia: A Model
for Selection by Infection, with a Focus on NAD Pp.
100-109
C.L. Miller
[Abstract] [Full
text article] [PMID:
19149605 PubMed - indexed for MEDLINE]
NAD+,
Sirtuins, and Cardiovascular Disease Pp.
110-117
N.M. Borradaile and J.G. Pickering
[Abstract] [Full
text article] [PMID:
19149606 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Nicotinamide Adenine Dinucleotide Biology
and Disease
Nicotinamide adenine dinucleotide (NAD) research has progressed
from the initial vitamin discovery phase in 1937 with the
cure for the NAD deficiency disease pellagra [1], to discoveries
in the 1950s of activities observed after application at pharmacological
doses. These latter applications include benefits to mental
health [2, 3] and lipodystrophy [4], where nicotinic acid
remains the most effective means of elevating HDL levels to
this current day.
Basic research reveals that NAD functions as a co-factor in
over 200 redox reactions and as a substrate for three categorical
classes of enzymes: NAD-dependent deacetylases (Sirtuins),
ADP-ribosyl transferases (most prominently, PARP-1), and ADP
cyclases (e.g. CD38). The effects of NAD deficiency are made
evident as the symptoms of the dreaded disease pellagra the
symptoms of which are often generalized and easily remembered
by the four D’s: dermatitis, diarrhea, dementia, and
death. These symptoms represent the wide range of functions
of NAD spanning from auto-immunity to mental function.
Modern molecular biology has revealed undeniably profound
trophic neuronal benefits afforded by maintaining NAD levels
working through SIRT-1 in studies of Slow Wallerian Degeneration
mouse [5]. These benefits extend to a wide range of neurodegenerative
disease models [6]. Two NAD-utilizing enzymes have emerged
as tremendous focus areas of pharmaceutical drug target investment:
PARP-1 (e.g. Inotek Pharmaceuticals bought by Genentech last
year) and SIRT-1 (e.g. Sirtris Pharmaceuticals, bought by
GSK). However, there are now known to be up to 18 potential
ADP-ribosyl transferase related genes and seven Sirtuin related
genes, some with specific nuclear or mitochondrial restricted
subcellular locations. While SIRT-1 and PARP-1 have mostly
been studied for their roles in cancer biology to date, the
role of NAD in auto-immune, neurodegenerative, and infectious
disease is rapidly increasing.
Looking to the future, this issue of Current Pharmaceutical
Design features leaders in the field relating NAD biology
to specific disease states. Focus is given to cancer, cardiovascular
disease, diabetes, multiple sclerosis, and tuberculosis-schizophrenia.
James B. Kirkland presents detailed analysis of endogenous
and pharmacological concentrations for respective NAD precursors
with emphasis on relevant pathway signaling, while Weihai
Ying et al. present a mechanisms of action regulating NADPH
oxidase and apoptosis. Shin-ichiro Imai covers the rate-limiting
enzyme controlling NAD recycling, NAMPT [7]. As the only known
extracellular enzyme in the NAD salvage pathway nicotinamide
mononucleotide working through NAMPT has unique potential
for regulating the immune system and beta cell function.
Cancer research has led the way in NAD experimental investigations
for many years. In this issue, Claudia Benavente with Elaine
and Myron Jacobson highlight increasingly appreciated NAD-centric
pathways including niacin-deficient activation of NADPH oxidase,
utilization of glutamine as an energy source during loss of
glycolysis, and the potential importance of Sirtuins in UV
damage responses. Meanwhile, Jo Milner brings to light the
importance of increased SIRT1 concentrations in cancer with
new insight on regulatory mechanisms involving micro-RNAs.
In 2004, for the first time in over half a century, Charlie
Brenner’s group verified that nicotinamide riboside
is a third form of vitamin B3 [8] (nicotinic acid and nicotinamide
being the other two). Thus began a renewed interest in medicinal
chemistry approaches to boosting NAD levels. Activators of
SIRT1 more potent than resveratrol continue to impress in
the context of metabolic diseases [9]. In this issue Anthony
Sauve presents novel approaches to boosting NAD levels with
special consideration for nicotinamide de-repression as a
potential mechanism for activating SIRT-1, while Eduardo N.
Chini focuses on the potential of CD38 inhibitors.
Other diseases including schizophrenia and multiple sclerosis
are of uncertain etiology but clearly involve dysregulation
in NAD metabolism that manifest as CNS pathogenesis. Penberthy
and Tsunoda emphasize the role of immune activation in controlling
cellular NAD sinks with likely critical roles in MS pathogenesis.
IDO and NAMPT1/PBEF/Visfatin tightly control local NAD concentrations
to manage T cell proliferation in the immune system and promote
cellular survival in response to acute stress respectively.
ADP cyclases in particular have gained appreciation as a depletor
of NAD in response to TNF alpha [10], while inteferons are
known to have the opposite effect on NAD levels in neural
tissues and macrophages through IDO activity [11-13]. Schizophrenics
have a weakened flush response to niacin treatment while tuberculosis
drugs are known to cause niacin deficiency and psychosis as
a side effect. Christine L. Miller elucidates these provocative
relationships with focus on the nicotinic acid high affinity
G-protein coupled receptor (GPR109a/HM74a) in schizophrenia
and describes an evolutionary model favoring schizophrenia
in the context of the survival bottleneck of tuberculosis
epidemics.
No NAD issue would be complete without a paper focused on
cardiovascular disease. Nicotinic acid corrects lipodystrophy
more effectively than any known therapeutic, while cardiovascular
disease is the number one killer in the western world. Thus,
Borradaile and Pickering describe the role of Sirtuin isoforms
in specific pathways affecting the cardiovascular system.
Today entire meetings are being organized to focus on the
importance of NAD (NAD 2008 and the next one is a FASEB Research
Conference scheduled for summer 2009: NAD Metabolism and Signaling).
NAD metabolism is one of the most complicated fields of biology.
Epigenetics, bioenergetics, redox, ROS production, and P450
metabolism, all have to be considered for elucidating any
NAD-dependent mechanism of action (MAO). With the information
explosion and the ever-increasingly refined user-friendliness
of neural networks-based systems biology approaches, it is
increasingly possible to make novel realizations. Gemini X
Pharmaceuticals used metabolomic approaches to identify promising
anti-cancer drug with a mechanism of action involving inhibition
of the rate-limiting enzyme controlling NAD biosynthesis (NAMPT)
in the cancer setting. Others have also discovered NAMPT inhibitors
exhibiting promising anti-cancer activities [14].
Concentrations of NAD and Sirtuins clearly exert potentially
rate-limiting roles conferring cellular survival advantages
for transformed cells and immune system cells, while also
exerting basic trophic functions in neurons and many other
tissues. Basic NAD MAO research continues to add to the appreciation
of the great potential for NAD therapeutics in clinical applications.
So frequently rate-limiting on the way to stress-induced cell
death, it is critical that we increase our understanding of
NAD function in the context of each individual disease. This
issue of Current Pharmaceutical Design is dedicated to new
insights relating NAD to disease.
References
[1] Elvehjem CA, Madden RJ, Strong FM, Woolley DW. Relation
of nicotinic acid and nicotinic acid amide to canine black
tongue. J Am Chem Soc 1937; 59: 1767.
[2] Hoffer A, Osmond H, Callbeck MJ, Kahan I. Treatment of
schizophrenia with nicotinic acid and nicotinamide. J Clin
Exp Psychopathol 1957; 18: 131-58.
[3] Hoffer A. Niacin therapy in psychiatry, Thomas: Springfield,
Ill; 1962.
[4] Altschul R, Hoffer A, Stephen JD. Influence of nicotinic
acid on serum cholesterol in man. Arch Biochem 1955; 54: 558-9.
[5] Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD
biosynthesis and SIRT1 activation prevent axonal degeneration.
Science 2004; 305: 1010-3.
[6] Coleman M. Axon degeneration mechanisms: commonality amid
diversity. Nat Rev Neurosci 2005; 6: 889-98.
[7] Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway
mediated by nicotinamide phosphoribosyltransferase regulates
Sir2 activity in mammalian cells. J Biol Chem 2004; 279: 50754-63.
[8] Bieganowski P, Brenner C. Discoveries of nicotinamide
riboside as a nutrient and conserved NRK genes establish a
Preiss-Handler independent route to NAD+ in fungi and humans.
Cell 2004; 117: 495-502.
[9] Feige JM, Lagouge M, Canto C, Strehle A, Sander, Houten
M, et al. Specific SIRT1 activation mimics low energy
levels and protects against diet-induced metabolic disorders
by enhancing fat oxidation. Cell Metab 2008; 8: 347-358.
[10] Iqbal J, Zaidi M. TNF regulates cellular NAD+ metabolism
in primary macrophages. Biochem Biophys Res Commun 2006; 342:
1312-8.
[11] Grant RS, Passey R, Matanovic G, Smythe G, Kapoor V.
Evidence for increased de novo synthesis of NAD in immune-activated
RAW264.7 macrophages: a self-protective mechanism? Arch Biochem
Biophys 1999; 372: 1-7.
[12] Grant RS, Naif H, Espinosa M, Kapoor V. IDO induction
in IFN-gamma activated astroglia: a role in improving cell
viability during oxidative stress. Redox Rep 2000; 5: 101-4.
[13] Grant R, Kapoor V. Inhibition of indoleamine 2,3-dioxygenase
activity in IFN-gamma stimulated astroglioma cells decreases
intracellular NAD levels. Biochem Pharmacol 2003; 66: 1033-6.
[14] Olesen UH, Christensen MK, Bjorkling F, Jaattela M, Jensen
PB, Sehested M, et al. Anticancer agent CHS-828 inhibits
cellular synthesis of NAD. Biochem Biophys Res Commun 2008;
367: 799-804.
W. Todd Penberthy
Department of Molecular Genetics
Biochemistry, and Microbiology
University of Cincinnati
231 Albert Sabin Way PO Box 670524
2938 CVC Mail Loc-0524
Cincinnati, Ohio
USA
Tel: 1(513) 919-3342
E-mail: wtpenber@yahoo.com
[Back to top]
[PMID:
19149597 PubMed - indexed for MEDLINE]
Niacin Status, NAD Distribution and ADP-Ribose Metabolism
J.B. Kirkland
[Full
text article]
Dietary niacin deficiency, and pharmacological excesses of
nicotinic acid or nicotinamide, have dramatic effects on cellular
NAD pools, ADP-ribose metabolism, tissue function and health.
ADP-ribose metabolism is providing new targets for pharmacological
intervention, and it is important to consider how the supply
of vitamin B3 may directly influence ADP-ribosylation reactions,
or create interactions with other drugs designed to influence
these pathways. In addition to its redox roles, NAD+
is used as a substrate for mono-, poly- and cyclic ADP-ribose
formation. During niacin deficiency, not all of these processes
can be maintained, and dramatic changes in tissue function
and clinical condition take place. Conversely, these reactions
may be differentially enhanced by pharmacological intakes
of vitamin B3, and potentially
by changing expression of specific NAD generating enzymes.
A wide range of metabolic changes can take place following
pharmacological supplementation of nicotinic acid or nicotinamide.
As niacin status decreases towards a deficient state, the
function of other types of pharmaceutical agents may be modified,
including those that target ADP-ribosylation reactions, apoptosis
and inflammation. This article will explore what is known
and yet to be learned about the response of tissues, cells
and subcellular compartments to excessive and limiting supplies
of niacin, and will discuss the etiology of the resulting
pathologies.
[Back to top]
[PMID:
19149598 PubMed - indexed for MEDLINE]
Roles of NAD+ / NADH and
NADP+ / NADPH in Cell Death
W. Xia, Z. Wang, Q. Wang, J. Han, C. Zhao,
Y. Hong, L. Zeng, L. Tang and W. Ying
[Full
text article]
A rapidly growing body of information has suggested that NAD
(including NAD+ and NADH)
and NADP (including NADP+
and NADPH) could be new fundamental factors in cell death:
Many studies have indicated key roles of poly (ADP-ribose)
polymerases and sirtuins --- two families of NAD-dependent
enzymes --- in cell death; and NAD may also affect cell survival
by influencing mitochondrial permeability transition, apoptosis-inducing
factor and GAPDH. NAD may further influence cell survival
by its effects on calcium homeostasis, gene expression and
immunological functions. Due to the crucial roles of oxidative
stress in cell death, NADPH may mediate cell death by its
major effects on oxidative stress: NADPH is a key factor in
cellular antioxidation systems; and NADPH oxidase is also
a major generator of oxidative stress. With growing information
about the novel biological properties of NAD and NADP, it
is likely that new roles of NAD and NADP in cell death and
various diseases will be elucidated. The elucidation may not
only improve our understanding about the fundamental mechanisms
of cell death, but also suggest new therapeutic targets for
a variety of diseases.
[Back to top]
[PMID:
19149599 PubMed - indexed for MEDLINE]
Nicotinamide Phosphoribosyltransferase (Nampt): A Link Between
NAD Biology, Metabolism, and Diseases
S.-i. Imai
[Full
text article]
New interest in NAD biology has recently been revived, and
enzymes involved in NAD biosynthetic pathways have been identified
and characterized in mammals. Among them, nicotinamide phosphoribosyltransferase
(Nampt) has drawn much attention in several different fields,
including NAD biology, metabolism, and immunomodulatory response.
The research history of this protein is peculiar and controversial,
and its physiological function has been a matter of debate.
Nampt has both intra- and extracellular forms in mammals.
Intracellular Nampt (iNampt) is an essential enzyme in the
NAD biosynthetic pathway starting from nicotinamide. On the
other hand, an extracellular form of this protein has been
reported to act as a cytokine named PBEF, an insulin-mimetic
hormone named visfatin, or an extracellular NAD bio-synthetic
enzyme named eNampt. This review article summarizes the research
history and reported functions of this unique protein and
discusses the pathophysiological significance of Nampt as
an NAD biosynthetic enzyme vs. a potential inflammatory cytokine
in diverse biological contexts.
[Back to top]
[PMID:
19149600 PubMed - indexed for MEDLINE]
NAD in Skin: Therapeutic Approaches for Niacin
C.A. Benavente, M.K. Jacobson and
E.L. Jacobson
[Full
text article]
The maintenance and regulation of cellular NAD(P)(H) content
and its influence on cell function involves many metabolic
pathways, some of which remain poorly understood. Niacin deficiency
in humans, which leads to low NAD status, causes sun sensitivity
in skin, indicative of deficiencies in responding to UV damage.
Animal models of niacin deficiency demonstrate genomic instability
and increased cancer development in sensitive tissues including
skin. Cell culture models of niacin deficiency have allowed
the identification of NAD-dependent signaling events critical
in early skin carcinogenesis. Niacin restriction in immortalized
keratinocytes leads to an increased expression and activity
of NADPH oxidase resulting in an accumulation of ROS, providing
a potential survival mechanism as has been shown to occur
in cancer cells. Niacin deficient keratinocytes are more sensitive
to photodamage, as both poly(ADP-ribose) polymerases and Sirtuins
are inhibited by the unavailability of their substrate, NAD+,
leading to unrepaired DNA damage upon photodamage and a subsequent
increase in cell death. Furthermore, the identification of
the nicotinic acid receptor in human skin keratinocytes provides
a further link to niacin’s role as a potential skin
cancer prevention agent and suggests the nicotinic acid receptor
as a potential target for skin cancer prevention agents. The
new roles for niacin as a modulator of differentiation and
photo-immune suppression and niacin status as a critical resistance
factor for UV damaged skin cells are reviewed here.
[Back to top]
[PMID:
19149601 PubMed - indexed for MEDLINE]
Cellular Regulation of SIRT1
J. Milner
[Full
text article]
The intersection between regulatory pathways responsive to
metabolic fluctuation on one hand, and to cellular stress
on the other, is a fascinating area within which NAD/NADH
responsive proteins play a major role [1, 2]. A key player
amongst these is SIRT1, a member of the mammalian sirtuin
family (SIRT1-7). SIRT1 is an NAD-dependent deacetylase with
critical functions in the maintenance of homeostasis and cell
survival. In this review I shall focus upon (i) the cellular
regulation of SIRT1 expression and (ii) the cellular regulation
of SIRT1 activity. In addition the distinction between basal
and stress-induced functions will be addressed: do they simply
reflect a sliding scale of response, or are they mechanistically
distinct? Elevated levels of SIRT1 are evident in cancer and
SIRT1 can function as a cancer-specific survival factor in
human cell lines. However, in a mouse model SIRT1 is reported
to function as a tumour suppressor. Possible explanations
for this apparent discrepancy will be considered. Given the
high profile of SIRT1 as a potential therapeutic target it
is clearly important to clarify its basal functioning in relation
to differentiation, cell type, intercellular communication,
and to age-related disease states including neurodegeneration
and cancer.
[Back to top]
[PMID:
19149602 PubMed - indexed for MEDLINE]
Pharmaceutical Strategies for Activating Sirtuins
A.A. Sauve
[Full
text article]
The sirtuins are protein modifying enzymes widely distributed
in all forms of life. The sirtuins are principally NAD+-dependent
protein acetyl-lysine deacetylases that reverse acetyl-modifications
of proteins. The sirtuins are implicated in a variety of adaptations
to reduced nutritional intake, and increase lifespan in several
model organisms, such as yeast, flies and worms. The human
sirtuins (SIRT1-7) have been identified to regulate a variety
of biological processes, such as glucose homeostasis, gluconeogenesis,
mitochondrial biogenesis, insulin secretion, adipogenesis
and adipolysis, apoptosis, senescence and metabolism. The
potency of sirtuins in regulating mammalian biological processes
invites consideration of them as potential drug targets. This
review considers small molecule approaches to activate sirtuins
in a bio-chemical and biological context. These approaches
include allosteric activation, which has been demonstrated
for the SIRT1 enzyme. Another approach discussed is enhancement
of NAD+ levels in cells,
since sirtuins appear to be responsive to increased cellular
NAD+. Finally, a sirtuin-specific
approach is considered that is called nicotinamide derepression.
This approach is designed to antagonize physiologic nicotinamide
inhibition of sirtuins as a means to upregulate sirtuin function.
Biological data that provides evidence of effectiveness of
these approaches in in vitro and in vivo
contexts is presented along with a discussion of the theoretical
considerations that underpin these strategies. Efficacies
and shortcomings of the various approaches are also discussed.
[Back to top]
[PMID:
19149603 PubMed - indexed for MEDLINE]
CD38 as a Regulator of Cellular NAD: A Novel Potential Pharmacological
Target for Metabolic Conditions
E.N. Chini
[Full
text article]
CD38 is a multifunctional enzyme that uses nicotinamide adenine
dinucleotide (NAD) as a substrate to generate second messengers.
Recently, CD38 was also identified as one of the main cellular
NADases in mammalian tissues and appears to regulate cellular
levels of NAD in multiple tissues and cells. Due to the emerging
role of NAD as a key molecule in multiple signaling pathways,
and metabolic conditions it is imperative to determine the
cellular mechanisms that regulate the synthesis and degradation
of this nucleotide. In fact, recently it has been shown that
NAD participates in multiple physiological processes such
as insulin secretion, control of energy metabolism, neuronal
and cardiac cell survival, airway constriction, asthma, aging
and longevity. The discovery of CD38 as the main cellular
NADase in mammalian tissues, and the characterization of its
role on the control of cellular NAD levels indicate that CD38
may serve as a pharmacological target for multiple conditions.
[Back to top]
[PMID:
19149604 PubMed - indexed for MEDLINE]
The Importance of NAD in Multiple Sclerosis
W.T. Penberthy and I. Tsunoda
[Full
text article]
The etiology of multiple sclerosis (MS) is unknown but it
manifests as a chronic inflammatory demyelinating disease
in the central nervous system (CNS). During chronic CNS inflammation,
nicotinamide adenine dinucleotide (NAD) concentrations are
altered by (T helper) Th1-derived cytokines through the coordinated
induction of both indoleamine 2,3-dioxygenase (IDO) and the
ADP cyclase CD38 in pathogenic microglia and lymphocytes.
While IDO activation may keep auto-reactive T cells in check,
hyper-activation of IDO can leave neuronal CNS cells starving
for extracellular sources of NAD. Existing data indicate that
glia may serve critical functions as an essential supplier
of NAD to neurons during times of stress. Administration of
pharmacological doses of non-tryptophan NAD precursors ameliorates
pathogenesis in animal models of MS. Animal models of MS involve
artificially stimulated autoimmune attack of myelin by experimental
autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination
using Thieler's murine encephalomyelitis virus (TMEV). The
WldS mouse dramatically
resists razor axotomy mediated axonal degeneration. This resistance
is due to increased efficiency of NAD biosynthesis that delays
stress-induced depletion of axonal NAD and ATP. Although the
WldS genotype protects
against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated.
In this review, we contrast the role of NAD in EAE versus
TMEV demyelinating pathogenesis to increase our understanding
of the pharmacotherapeutic potential of NAD signal transduction
pathways. We speculate on the importance of increased SIRT1
activity in both PARP-1 inhibition and the potentially integral
role of neuronal CD200 interactions through glial CD200R with
induction of IDO in MS pathogenesis. A comprehensive review
of immunomodulatory control of NAD biosynthesis and degradation
in MS pathogenesis is presented. Distinctive pharmacological
approaches designed for NAD-complementation or targeting NAD-centric
proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined
towards determining which approach may work best in the context
of clinical application.
[Back to top]
[PMID:
19149605 PubMed - indexed for MEDLINE]
The Evolution of Schizophrenia: A Model for Selection by Infection,
with a Focus on NAD
C.L. Miller
[Full
text article]
Schizophrenia is a common, debilitating mental illness that
has persisted over the generations. For a disease with a strong
genetic component, such prevalence has been difficult to understand
in evolutionary terms. A model for its prevalence as a phenotype
is presented in this manuscript, based on reports of specific
differences in gene expression, metabolite levels and historical
epidemiology. The selective force that underlies the proposed
model is tuberculosis, a scourge of huge proportions that
itself evolved to interact with the human host in a manner
ensuring both its long term persistence in the host and its
transfer to other carriers prior to the host’s unfortunate
death. The focal point of the interaction between humans and
M. tuberculosis is hypothesized to be the de
novo synthesis of NAD via activation of the
kynurenine pathway. The strategy that M. tuberculosis
employed to circumvent this aspect of the host’s response
to mycobacterial infection, and how that strategy interacted
with a poor diet to force human evolution towards increased
risk for schizophrenia, forms the basic premise of this paper.
The model has implications for treatment of both diseases
and generates hypotheses to be tested.
[Back to top]
[PMID:
19149606 PubMed - indexed for MEDLINE]
NAD+, Sirtuins, and Cardiovascular
Disease
N.M. Borradaile and J.G. Pickering
[Full
text article]
Cardiovascular disease (CVD) is the most prevalent disease
worldwide and there is intense interest in pharmaceutical
approaches to reduce the burden of this chronic, aging-related
condition. The sirtuin (SIRT) family of NAD+-dependent
protein deacetylases and ADP-ribosyltransferases have emerged
as exciting targets for CVD management that can impact the
cardiovascular system both directly and indirectly, the latter
by modulating whole body metabolism. SIRT1-4 regulate the
activities of a variety of transcription factors, coregulators,
and enzymes that improve metabolic control in adipose tissue,
liver, skeletal muscle, and pancreas, particularly during
obesity and aging. SIRT1 and 7 can control myocardial development
and resist stress- and aging-associated myocardial dysfunction
through the deacetylation of p53 and forkhead box O1 (FoxO1).
By modulating the activity of endothelial nitric oxide synthase
(eNOS), FoxO1, and p53, and the expression of angiotensin
II type 1 receptor (AT1R), SIRT1 also promotes vasodilatory
and regenerative functions in endothelial and smooth muscle
cells of the vascular wall. Given the array of potentially
beneficial effects of SIRT activation on cardiovascular health,
interest in developing specific SIRT agonists is well-substantiated.
Because SIRT activity depends on cellular NAD+
availability, enzymes involved in NAD+
biosynthesis, including nicotinamide phosphoribosyltransferase
(Nampt), may also be valuable pharmaceutical targets for managing
CVD. Herein we review the actions of the SIRT proteins on
the cardiovascular system and consider the potential of modulating
SIRT activity and NAD+ availability
to control CVD.
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