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Transgenic cetp dahl salt sensitive (tg53) rat model

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Transgenic cetp dahl salt sensitive (tg53) rat model

  1. 1. Transgenic CETP Dahl Salt-sensitive (Tg53) Rat Model “Is it promising enough?”
  2. 2. 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@bu.edu
  3. 3. 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
  4. 4. Modeling vulnerable plaque – an underestimated challenge Analysis of coronary artery disease at end-stage plq hge plq eros’n plq fissure plq thombosis occlus’n Pigeon: Carneau, Show Racer * aortic root nr + nr nr + Monkey: a. Cynomolgus b. African green c. Rhesus + + nr nr nr nr nr nr nr nr nr nr + + Pig: a. thiouracil + xrad’n 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 + + + + + [nr, not reported; +, present]
  5. 5. 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
  6. 6. Elements of a “promising model” Tg53 rat model simulates human coronary heart disease (CHD) plaque site  plaque predilection site = coronary arteries  in contrast to: aortic root plaque predilection site in mouse models described to date Tg53 end-stage plaques in proximal right coronary artery [PTAH stain, 40x original mag] RV Ao
  7. 7. 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
  8. 8. 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 7:831, 2001].  “end-stage” simulates cardiac endpoints of CHD • (+) cardio-respiratory distress • (+) signs of heart failure
  9. 9. Elements of a “promising model” Tg53 rat model simulates human coronary heart disease (CHD) plaque progression  “culprit” plaque features: foam-cell rich, paucity of smcs, leukocyte adhesion, intraplaque thrombi, erosion, plaque shoulder susceptibility Masson – trichrome stain 400x orig mag PTAH; 1000x orig mag
  10. 10. Elements of a “promising model” Masson – trichrome; 1000x orig mag Tg53 rat model simulates human coronary heart disease (CHD) plaque progression  “culprit plaque features: foam-cell rich, intraplaque hemorrhage, paucity of smcs, lipid core > 1/3 of plaque volume smc α-actin, Fast red im-stn; 400x
  11. 11. Elements of a “promising model” Tg53 rat model simulates human coronary heart disease (CHD) plaque progression  “culprit” plaque features: fibrin-positive thrombosis in proximal coronary lesions; none detected in more distal stable lesions PTAH: fibrin(+) thrombus; prox lesion PTAH: distal stable lesion
  12. 12. Elements of a “promising model” Tg53 rat model simulates human coronary heart disease (CHD) plaque progression  recapitulates lesion heterogeneity of “culprit” plaques associated with human acute coronary syndromes PTAH: thick cap, smc-rich, but with intraplq hge & thrombosis, IEL disrup’n PTAH: reduced cap & smc; foam-cell rich; + intraplq hge & thrombosis,
  13. 13. 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
  14. 14. 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
  15. 15. 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: a. investigation of mechanisms of coronary plaque development not possible in humans b. methodical in vivo investigation of novel intervention targets c. maximization of genomic-based technologies aimed at the investigation of mechanisms and targets
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. • ... can’t 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 ...  Tg53 rat model – “is it promising enough?”
  20. 20. Acknowledgment • This work is supported by grants from the National Institutes of Health and American Heart Association.

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