Transgenic CETP Dahl Salt-sensitive (Tg53) Rat Model

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Transgenic CETP Dahl Salt-sensitive (Tg53) Rat
Model

• Is it promising enough?

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• Victoria L. M. Herrera, M.D.
• Associate Professor of Medicine
• Section of Molecular Genetics
• Whitaker Cardiovascular Institute
• Boston University School of Medicine
• 700 Albany Street W609, Boston MA 02118
• vherrera_at_bu.edu

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Tg53 rat model is it promising enough?

• Question analyzed
• a provocative but necessary question posed by
  Symposium organizers
• modeling the vulnerable plaque has been an
  underestimated challenge
• a review of multi-species animal models of
  atherosclerosis from the 1960s underscores this
  challenge

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Modeling vulnerable plaque an underestimated
challenge
Analysis of coronary artery disease at end-stage plq hge plq erosn plq fissure plq thombosis occlusn
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Pig a. thiouracil xradn b. FHC hyperLDL-emia nr nr nr some some
Rabbit WatanabeHHL coronary ostia nr nr nr nr
Mouse ApoE/LDLr knockout nr nr nr nr
Rat Tg53 rat model
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Elements of a promising model

• Simulation of coronary artery disease
• plaque site
• disease course
• plaque progression
• Model advantages as experimental system
• reproducibility
• duration to valid endpoints
• defined genetic background
• accessible phenotype manipulation
• Model value and potential
• as investigative instrument
• as pre-clinical platform

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Elements of a promising model
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Elements of a promising model

• Tg53 rat model simulates human coronary heart
  disease (CHD)
• disease course
• risk factors consistent with human CHD
• hypertension exacerbates phenotype
• atherogenic lipid profile increased total
  cholesterol and triglyceride levels, low HDL,
  increased VLDLc and VLDLtg, increased small LDLc
• hyperlipidemia increases with age

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Elements of a promising model

• Tg53 rat model simulates human coronary heart
  disease (CHD)
• disease course
• decreased survival compared with non-transgenic
  non-hyperlipidemic, hypertensive, Dahl S rat
  controls on regular rat chow Nat Med 5 383,
  1999 Mol Med 7831, 2001.
• end-stage simulates cardiac endpoints of CHD
• () cardio-respiratory distress
• () signs of heart failure

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Elements of a promising model
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Elements of a promising model
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Elements of a promising model
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Elements of a promising model
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Elements of a promising model

• Tg53 rat model advantages as experimental system
• reproducibility and robustness of phenotype
• lipid profile increased total cholesterol and
  triglycerides predominantly in VLDL, low HDL
• culprit plaque phenotype in proximal right
  coronary artery
• stable occlusive plaque in smaller coronary
  arteries
• reasonable duration to valid endpoints
• 6-9 month range of proximal coronary plaque
  development on regular rat chow eccentric
  macrophage-foam cell rich plaque which progresses
  to culprit plaque at endstage

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Elements of a promising model

• Tg53 rat model advantages as experimental system
• defined genetic background eliminates
  differential genetic susceptibility as confounder
• inbred Dahl salt-sensitive hypertensive rat
  strain
• accessible phenotype manipulation onset and
  course of hyperlipidemia and coronary artery
  disease can be experimentally manipulated
• Western Type Diet (0.15 cholesterol) accelerates
  onset and levels of hyperlipidemia
• low salt diet (0.0038 NaCl), which reduces level
  of hypertension, attenuates coronary artery
  disease hence increasing survival

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Elements of a promising model

• Tg53 rat model value and potential
• identical genetic background and ability to
  regulate environmental factors allows well-
  controlled in vivo studies for cross-talk
  pathogenesis
• investigation of mechanisms of coronary plaque
  development not possible in humans
• methodical in vivo investigation of novel
  intervention targets
• maximization of genomic-based technologies aimed
  at the investigation of mechanisms and targets

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Elements of a promising model

• Tg53 rat model value and potential
• coronary-specific experimental design for
  coronary artery-disease studies with cumulative
  evidence of vessel-specific genetic factors, the
  Tg53 coronary-specific phenotype is key
• combinatorial modeling well characterized inbred
  rat strains allow cross-breeding for interaction
  studies relevant to human disease
• hypertension
• diabetes
• obesity

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Elements of a promising model

• Tg53 rat model value and potential
• as investigative tool invaluable new insight
  distinct from that observed in current other
  models as a beginning,
• 1. prelude to culprit plaque the eccentric
  macrophage foam-cell rich lesion becomes the
  culprit plaque, thus experimentally capturing
  the beginning of the vulnerable plaque
• 2. differential pathway hypothesis proximal
  vulnerable-culprit coronary lesions develop
  distinct from more distal stable coronary plaques
• 3. lesion heterogeneity paradigm given identical
  genetic background and environmental factors,
  lesion heterogeneity at end-stage reflect
  stochastic endpoints of a common pathogenic
  framework

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Elements of a promising model

• Tg53 rat model value and potential
• as pre-clinical platform
• identical genetic background
• regulated environmental factors
• robust coronary phenotype
• instrumentation accessibility
• rat physiological and pharmacological information
  database
• allow continuity of comparative analysis for
  successful new intervention and prevention
  strategies

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Tg53 rat model is it promising enough?

• ... cant promise the world but along with
  other animal models, can together make a better
  promise,
• but then again, which model can be promising
  enough since even humans although they are the
  ultimate benchmarks make terrible models, if
  not the worst, for human coronary artery disease
  ...
• ?

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Acknowledgment

• This work is supported by grants from the
  National Institutes of Health and American Heart
  Association.