Download ATVB 2011

Update from the
IAS 2012
Jonathan Silberberg
March 2012
overview
New pathways to chd
Hdl therapy
Mast cells, T & B cells, chemokines
microRNAs
AAA, diabetes, alzheimers
796 abstracts
niacin
• General agreement that AIM-high
(NEJM Nov 2011) was underpowered
• Awaiting HPS2-THRIVE n=25000
• Effects on HDL and LDL
• Induces heme-oxygenase 1, cellular
protective, inhibits vascular
inflammation in non-lipid models
Kastelein, Wu, others
HDL and diabetes
• Low HDL predicts future diabetes
• Mechanism is non-insulin mediated
glucose uptake, via AMP kinase
• Cellular fuel gauge in active tissues eg
skeletal muscle, preserves ATP
• HDL rx lowers blood glucose and also
increases insulin, rescues beta cell
B Kingwell, Baker IDI
Reverse transport
ABC-A1
SRB-1
reverse transport
reverse transport
+ free
cholesterol
apoA1
phospholipid
LCAT
HDL3
CETP vldl
HDL2
HDL infusion
•
Rvx-8
• Orally active, increases apoA1
• SUSTAIN trial, ASSURE ivus
•
Cerenis cer001
• More potent than apoA1 Milano
• Ivus trial ChiSquare AHA 2012
HDL infusion (2)
•
CSL112
• Nascent HDL discs
• Increase ABC-a1 dependent efflux
• ACC 2013
•
Delipidated HDL
• Brewer et al JACC 2010;55:2727
HDL: questions
• Does it matter whether HDL acquires
cholesterol via ABC-A1 (preBeta and
delipidated HDL) or ABC-G1 (mature
HDL) transporters?
• Infusions show reduction in plaque
volume, vessel wall inflammation
• Equivalent to 2 y statin treatment
HDL controversies
•
•
Is CETP inhibition the opposite
of pre-beta HDL treatment?
Which HDL functions need
cholesterol efflux, and which are
due to other proteins
associating with HDL?
microRNAs
•
“just another way to control
gene expression”
• Or are they special?
• One microRNA can repess numerous
mRNAs
• Stable in plasma, hide in lipid carriers
eg LDL, HDL, exosomes
ATVB 2011; 31:2383
ATVB 2011; 31:2378
microRNAs from plaque
• 250 from monocytes, 80 exported
• 140 from dendritic cells, 80 exported
• Each cell type transmits unique
signature to HDL via microRNA
• Delivers inflammatory signal to liver
• How organs communicate with each
other
miR223
•
most abundant in plaque
• Upregulated in FH (LDL receptor
defect); one of 22 miRs abnormal
• Downregulates several genes and
enzymes involved in lipid metabolism
• Opposite in NASH
Mast cells
•
Contribute to plaque rupture
• Subendothelial, accumulate in
neovascularised areas
• Immediate degranulation, chymase
• Activates MMPs (collagenases),
degrade fibronectin which anchor SMC
to matrix. Apoptosis from loss of
survival signal
T cell response to oxLDL
• Dendritic cells patrol artery, present
antigen to T-cells in regional LN
• Effector T cells are specific; reenter
arterial wall & initiate secondary
cascade with macrophages etc
• Il-10 redirect dendritic cell to Treg,
tolerant phenotype
• prospects for specific immunorx
Hanson Nature Immunol 2011
B cells
•
B1 cells innate immunity
• Antigen independent, atheroprotective,
remove oxLDL and apoptotic debris
•
B2 adaptive immunity
• Bone marrow derived, activated by
BAFF, targetted by rituximab
• Expressed in unstable plaque, predicts
events
Mallat, Cambridge
chemokines
•
•
•
•
Mouse models of early atherosclerosis
Noel & Weber Nature Medicine 2011
Cell recruitment, survival
Specific regulation, not general
antiinflammatory effect
• Best target platelet-derived peptide
• ?regional delivery of miRNA
Alzheimers >65yo
• CNS lipoproteins resemble HDL but
major apo is E, not A1
• aBeta protein fragment is degraded by
macrophages after lpE uptake, needs
lipid-rich particle
• E4/E4 onset 17 y early
• E4/other onset 10y early
• ?LXR agonists for short-term
Wellington Vancouver