Transcript Rosuvastatin and Cardiovascular Events in Patients Undergoing

Fellow Seminar
• Topic: Vitamin D: a pleiotropic
hormone
Comment ：洪振傑 醫師
報告人員：F2 張春偉
報告時間：99-09-15
OUTLINE
• VITAMIN D – NORMAL METABOLISM
• VITAMIN D IN BONE & CALCIUM
HOMEOSTASIS
• VITAMIN D & CANCER
• VITAMIN D AS IMMUNE MODULATOR
• CARDIOVASCULAR & METABOLIC
ACTIONS
• RENAL PROTECTION
• CLINICAL PERSPECTIVES
VITAMIN D - NORMAL
METABOLISM
• In kidney, mitochondria of epithelial
cells in the proximal nephron
reabsorption of 25-hydroxyvitamin D +
DBP from tubular fluid
– By megalin-dependent mechanism
• Calcitriol is then released into peritubular
blood
– Circulates in plasma again bound to DBP
Vitamin D binding protein
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DBP
~ 58-kDa protein synthesized in the liver
Human serum levels: 4 - 8 μM
Half life: 3 days
The parent vitamin D, 25(OH)D, &
1,25(OH)2D are carried in the circulation
by DBP
– But the greatest affinity is for 25(OH)D
Vitamin D binding protein
• Primary role
– Maintain stable serum stores of vitamin D
metabolites & modulate the rates of
bioavailability, activation, & end organ
responsiveness
• Deficiency of DBP
– Occur in nephrotic syndrome due to urinary
protein losses
– Leading to low 25(OH)D serum levels
Genomic mechanism
• At the cellular level, receptor (megalin)–
mediated endocytosis of both calcidiol &
calcitriol
• Inside the cell, 1,25(OH)2D
– Inactivated by mitochondrial 24-hydroxylase
– Or bind to the VDR in the cytoplasm
• VDR-ligand binding occurred => VDR
translocates to the nucleus
• => Heterodimerizes with the retinoid X
receptor
Genomic mechanism
• This complex binds the vitamin D
response element of target genes
• Recruits transcription factors &
corepressors/activators that modulate the
transcription
• These corepressors & coactivators
appear to be specific for the ligand
– Different forms & analogs of vitamin D may
produce different effects
Nongenomic
• Exert biologic effects over periods of time
that are too short to be explained by
genomic mechanisms
• A discrete receptor, or membraneassociated protein
– Distinct from the VDR may mediate these
rapid nongenomic actions
Transcaltachia
• Increases in intestinal Ca transport within
10 - 15 minutes after adding 1,25dihydroxyvitamin D to fluid used to
perfuse the lumen of the proximal small
intestine
Impact of Chronic Kidney Disease
on Vitamin D Metabolism
• Cross-sectional studies
– 1,25-dihydroxyvitamin D decrease
progressively as renal function declines
– Reductions in renal synthesis
• Adversely affects intestinal Ca
absorption => modest reductions in
serum Ca concentration
• => Hypocalciuria
• Several mechanisms involved
Consequences of Impaired
Renal Calcitriol Synthesis in
Chronic Kidney Disease
• Calcitriol modulates the expression of
several key proteins responsible for the
transepithelial movement of Ca
– Not only in intestine but also in kidney
• Calbindins
– Vitamin D-dependent proteins
– Buffer free Ca within the cytoplasm of
epithelial cells in Ca-transporting epithelia
– Translocation of Ca from the apical to the
basolateral cell membrane
• Calcitriol + Ca modulates the expression
of 2 proteins
• Vanilloid family of transient receptor
potential (TRP) proteins
• TRPV-5 & TRPV-6
• Constitutively activated Ca channel
• Mediates Ca uptake across the apical
membrane of renal & intestinal epithelial
cells
Extrarenal Calcitriol
Synthesis
• Other tissues also express the 25hydroxyvitamin D-1-α-hydroxylase
• => 1,25-dihydroxyvitamin D synthesis
regulated in a tissue-specific manner
• => serve as autocrine or paracrine
VITAMIN D IN BONE &
CALCIUM HOMEOSTASIS
• 1,25(OH)2D3
– Major calcitropic hormone
– Keep the plasma Ca2+ within narrow limits
– Renal production regulated by 2 hormones
• PTH
– Hypocalcemia => secretion of PTH by the
parathyroid gland
– PTH targets the kidney
• Decrease Ca2+ excretion, inhibit phosphate
reabsorption, & stimulate 1,25(OH)2D3 production
FGF23
• 1,25(OH)2D3 stimulates the secretion of
FGF23 by the osteocytes
• Major phosphaturic hormone
• Inhibiting renal phosphate reabsorption
• By the specific transporter NaPiT2a
• Decrease renal production of
1,25(OH)2D3
• Genetic deficiencies in 1,25(OH)2D3
– Loss of CYP27B1 or VDR
– => hypocalcemia, hyperparathyroidism,
hypophoshatemia, rickets, & osteomalacia
• The phenotype can largely be corrected
by administration of a high Ca diet
– Bypasses 1,25(OH)2D3 -mediated, Ca2+
absorption
- Endocr Rev 2008;29: 726–776
• Reintroducing VDR in the intestine of
VDR null mice rescued the hypocalcemia
& the bone phenotype
- Gastroenterology 2009; 136:1317–1327
- J Bone Miner Res 2008; 23: S104
• The proteins involved in this active
intestinal Ca2+ transport remain poorly
defined.
• TRPV6, Calbindin
– Main mediators of 1,25(OH)2D3 -induced
intestinal Ca2+ absorption
• Inactivation of TRPV6 & calbindin D9k
not impair intestinal Ca2+ absorption
when dietary Ca intake is normal
– => compensatory proteins
• TRPV6 is critical for Ca2+ absorption
when dietary Ca intake is low
– Impaired intestinal Ca2t absorption in
TRPV6 null mice on a low Ca diet
- J Bone Miner Res 2007; 22: 274–285
- Endocrinology 2008; 149: 3196–3205
• Hypothesis: 1,25(OH)2D3 action not only
affects transcellular but also paracellular
Ca2+ transport
• Regulate tight junction permeability in
the intestine by modifying the expression
of several tight junction proteins
– Claudin-2 & claudin-12
- Mol Biol Cell 2008; 19: 1912–1921
• TRPV5 is definitely critical for renal Ca2+
reabsorption
• TRPV5 null mice
– Profound Ca2+ wasting
– With compensatory increased intestinal Ca2+
absorption
– Due to high 1,25(OH)2D3 serum levels, &
normocalcemia as a result
- J Clin Invest 2003; 112: 1906–1914
Direct effect of 1,25(OH)2D3
on bone homeostasis?
• 1,25(OH)2D3 stimulate bone resorption
– Increasing the expression of
osteoclastogenic factors in osteoblasts
• Receptor activator of nuclear factor kB ligand
• 1,25(OH)2D3 -mediated signaling in
regulating the activity of chondrocytes &
osteoblasts
– During endochondral bone formation & bone
homeostasis
• Aberrant growth plate development in
VDR-deficient mice appears before the
onset of hypocalcemia
• High Ca diet corrected all aspects of the
phenotype of CYP27B1-deficient mice,
except long bone growth
- Endocr Rev 2008;29: 726–776
• Mice lacking VDR expression in
chondrocytes
– Normal growth plate
– But develop a transient phenotype of
increased bone volume postnatally
– Due to decreased expression of the
angiogenic factor VEGF & the
osteoclastogenic factor receptor activator of
nuclear factor kB ligand in chondrocytes
- J Clin Invest 2006; 116: 3150–3159
• 1,25(OH)2D3 -mediated signaling in
chondrocytes
• Necessary for timely vascular invasion &
osteoclastogenesis during bone growth
VITAMIN D & CANCER
• Several large-scale epidemiological
studies have shown an inverse
correlation between exposure to
sunlight (the major source of vitamin D)
or vitamin D intake & risk of colorectal,
breast, & prostate cancer
Colorectal cancer risk
• Am J Prev Med 2007; 32: 210–216
– Meta-analysis
– 51% lower incidence of colorectal ca
• Highest serum 25(OH)D3 quintile (82 nmol/l)
compared to the lowest quintile (<=30 nmol/l)
• Aliment Pharmacol Ther 2009; 30:113–
125
– Meta-analysis
– Lower serum 25(OH)D3 inversely
associated with colorectal cancer
Am J Prev Med 2007; 32: 210–216
Am J Prev Med 2007; 32: 210–216
Aliment Pharmacol Ther 2009; 30:113–125
• NEJM 2006; 354: 684–696
– Randomized, double-blind, placebocontrolled trial involving 36,282
postmenopausal women from 40 Women’s
Health Initiative centers, combined treatment
of vitamin D3 (400 IU per day) & Ca
– Not decrease colon cancer risk
• Am J Clin Nutr 2007; 85: 1586–1591
– Much smaller RCT
– 1100 IU per day of vitamin D3 + Ca
– Decreased the overall cancer risk
Am J Clin Nutr 2007; 85: 1586–1591
RR=0.232,
P<0.005
RR=0.587,
P=0.147
Breast cancer risk
• Positive study in the US & Europe
• Best Pract Res Clin Endocrinol Metab
2008; 22: 587–599
– UK
– Women with 25(OH)D3 levels < 50nmol/l
OR=3.54 for breast cancer risk compared
with women with levels >50 nmol/l
• Negative in other epidemiological studies
Cancer Epidemiol Biomarkers Prev 2005; 14: 1991–1997
• Prostate cancer
– Association with 25(OH)D3 status less clear
than for colorectal cancer
• Overall cancer outcome
– Association remains ambiguous
Am J Epidemiol 2009; 169: 1223–1232
• Supraphysiological doses of
1,25(OH)2D3
– Potent growth-inhibitory & prodifferentiating effects on a variety of cell
types
• VDR-/- mice hyperproliferation in the
colon & mammary gland
– Not develop cancer spontaneously but
predisposed to cancer when challenged with
carcinogenic agents
• 1,25(OH)2D3 inhibits cell growth by
hampering the transition from the G1
to the S phase of the cell cycle
• 1,25(OH)2D3 accumulates cells in the G1
phase
– Targeting cell-cycle regulators in a direct or
indirect way
• Cyclin-dependent kinase inhibitor
p21(waf1/cip1)
– Directly activated by 1,25(OH)2D3
– Through a vitamin D responsive element in
its promoter region
• Increase of cyclin-dependent kinase
inhibitor p27(kip1) protein levels
– Posttranslational modifications
– 1,25(OH)2D3-induced repression of the
miR181 family => accumulation of p27(kip1)
• Decrease cyclin D1 & cyclin E expression
• Decrease activity of complexes between
cyclins & cyclindependent kinases
– Influences the phosphorylation status of the
retinoblastoma pocket protein family
– Preventing the release of the E2F
transcription factors 1, 2, 3
– Keeps the inhibitory complexes of E2F4 &
E2F5 with p107 & p130 pocket proteins on
the promoter of cell-cycle target genes
Endocr Rev 2008;29: 726–776
• Presence of the VDR in tumors + growthregulatory effect of 1,25(OH)2D3
– Use of this compound in cancer prevention
and/or treatment
• Small trials
– High weekly dose of 1,25(OH)2D3 instead of
daily administration was safe & combination
therapies were well tolerated
ASCENT phase III clinical
trial
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Novacea, South San Francisco, CA, USA
Large cohort of patients (950)
Anrogenindependent prostate cancer
Control arm: Taxotere every 3 weeks
Weekly high dose of 1,25(OH)2D3 (DN101) + once-weekly Taxotere
• Terminated 30 weeks earlier
– Unexplained imbalance of deaths between
the treatment & control group
TX 522
• Inecalcitol; Hybrigenics, Paris, France
• Structural analogs of 1,25(OH)2D3
• Clear dissociation between
antiproliferative & calcemic effects
• In phase II in patients with hormonerefractory prostate cancer
TX 522
• Preliminary results
– 27 of the 31 patients
– Inecalcitol (at different doses up to 600 mg
per day) & Taxotere during 18 weeks
– Decrease in PSA levels >30% within 3
months of initiation of treatment
– Without any changes in Ca parameters
VITAMIN D AS IMMUNE
MODULATOR
• Exposure of skin to UVB =>
immunosuppression
• Part of this effect is mediated through
synthesis of vitamin D & activation to
its active form 1,25(OH)2D3 under the
influence of UVB
• Receptors for vitamin D have been
described in most cells of the immune
system & many immune cells
• Activate 25(OH)D3 to 1,25(OH)2D3
– Within the immune system a paracrine
presence of 1,25(OH)2D3
Mol Aspects Med 2008; 29: 376–387
• Immune stimuli => immune cell =>
secretion of 1,25(OH)2D3
• Crucial immune stimulus: interferongamma
• Other macrophage
activators/differentiators simultaneously
to activate a complex network of
signaling pathways
– LPS, phorbol myristate acetate, or TNF-α
• TLR4 activation & TLR2/1 triggering
– Able to induce 1α-hydroxylase in human
macrophages
– Induction of an antimicrobial response
• 1,25(OH)2D3 -metabolizing enzyme,
CYP24A1
– 24-hydroxylation
– Expressed by antigen-presenting cells
• 1,25(OH)2D3 enhanced capacity of
innate antibacterial defense
• More tolerogenic profile toward
autoimmune phenomena
• Dendritic cell (DC) & other APCs
– Langerhans cells in skin
– Central to the effect of vitamin D
• Maturation, differentiation, & function of
DCs affected, with downregulation of
MHC class II & costimulatory
molecules
– CD40, CD80, & CD86
• => Tolerance-promoting phenotype
• DC alterations + effects on cytokine
secretion by the DC
– Favoring IL10 & inhibiting IL12
• => T-cell function affected
– Promoting development of Th2 lymphocytes
within the CD4+ subset
– Also affecting CD8+ CTL development
T lymphocytes
• Can be direct targets for 1,25(OH)2D3
– Inhibition of several cytokines, INF-r & IL-17
– Stimulation of others such as IL-4
• 1,25(OH)2D3 affects the expression of
chemokine receptors on the surface of T
lymphocytes
– Determine the target tissue where any
primed T lymphocytes will migrate to
Regularory T cell
• Tregs
• 1,25(OH)2D3 has been shown to induce
Tregs
Semin Immunol 2004;16: 127–134
Monocyte/macrophage
• Another important target cell of
1,25(OH)2D3
• TLR activation
• Responsible for antibacterial & antiviral
defenses
• 1,25(OH)2D3 promote secretion of
antibacterial products
– Cathelicidin
- Science 2006; 311:1770–1773
Vitamin D deficiency &
autoimmunity
• Epidemiological studies
– Type 1 diabetes, multiple sclerosis,
inflammatory bowel disease
• Preclinical animal models
– Vitamin D deficiency especially early in life
enhances such autoimmune diseases
• Need prospective intervention studies
CARDIOVASCULAR &
METABOLIC ACTIONS
• Vitamin D-deficient rats or mice with
deletion of VDR or 1α-hydroxylase
– High renin hypertension with ultimately
cardiac hypertrophy
• Selective VDR deficiency in cardiac
myocytes can reproduce the effects.
• Am J Hypertens 2009; 22: 816
– Normotensive & hypertensive Caucasian,
Hispanic, or African Americans
– Lower serum 25(OH)D with higher BP
• Endocr Rev 2008;29: 726–776
– Normotensive & hypertensive patients
– BP inversely correlated with plasma
1,25(OH)2D & renin concentrations
• Low 25(OH)D & metabolic syndrome
– Obesity, insulin resistance, type 2 diabetes
• Only very small scale intervention studies
using vitamin D or its active hormone on
BP or other aspects of the metabolic
syndrome
Endocr Rev 2008;29: 726–776
Endocr Rev 2008;29: 726–776
RENAL PROTECTION
KI (2010) 77, 1000–1009;
CLINICAL PERSPECTIVES
• Major function of 1,25(OH)2D3 /VDR
– Control the Ca & bone homeostasis
• Combined presence of 25(OH)D3-1αhydroxylase + VDR in several
nonclassical tissues introduced the
concept of a paracrine/autocrine
function for 1,25(OH)2D3 outside the Ca
& bone metabolism.
• 1,25(OH)2D3 capable of regulating cell
differentiation & proliferation of normal
(immune) cells & malignant cells
• Poor vitamin D status is linked with all
major diseases causing the majority of
human morbidity
– Cancer, immune diseases, metabolic
syndrome, hypertension, & cardiovascular
risk factors
• The optimal daily dosage is highly
debated
• Most RCTs used 600–1000 IU of vitamin
D3 per day
– Decrease the risk of fractures & falls in the
elderly
• Serum 25(OH)D concentration
– Should > 20 ng/ml (or 50 nmol/l)
– Probably even 30 ng/ml (80 nmol/l) in
patients with impaired renal function
• Mean level of 25(OH)D around the world
– ~ 20 ng/ml
• US NHANES IV
– < 30 ng/ml
• Large part of the human population mildly
vitamin D deficient
• Patients with CKD have a greater than
normal risk for bone diseases, cancer,
immune disorders, & increased CV
mortality
• A number of observational studies have
shown that treatment of hemodialysis
patients with active vitamin D analogs
decreases (cardiovascular) mortality.
• Overall contribution of combined
impaired 25(OH)D3–1,25(OH)2D3 status
on morbidity & mortality in patients with
CKD may be substantial but needs
further RCTs.
Endocr Rev 2008;29: 726–776
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