Atherosclerosis 1
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Professor Moshe Wolman: Pioneer in Histochemistry
Macrophages and Atherosclerosis
Histopathology of atherosclerosis Raymond Coleman, Tony Hayek, Shlomo Keidar & Michael Aviram Rappaport Faculty of Medicine Haifa, Israel
Cardiovascular disease: the major cause of premature mortality
Coronary blockage
Risk factors for atherosclerosis • • • • • • • • • • • • • • •
Genetic (inherited) Gender (maleness) Intimal injury Vascular hemodynamics (shear stress) Hypertension Inflammation Infection (Chlamydia) and immune responses (?) Lipid disorders (hypercholesterolemia) Diabetes Cigarette smoking Elevated homocysteine Elevated iron Elevated C reactive protein Lifestyle (sedentary, eating disorders, Western diet) Cardiovascular aging changes
Risk factors? More than you imagine
Hypercholesterolemia is widely regarded as a major risk factor for atherosclerosis
Clinton’s diet
Apolipoprotein E-deficient mice • Since the early 1990s the apolipoprotein Edeficient mouse has provided a useful animal model of hypercholesterolemia and the progressive development of atherosclerotic plaque similar to that of humans • The earliest stages of plaque development are seen within 6-8 weeks • Quantitative image analysis of plaque permits research on the effectiveness of drugs or food additives in retarding plaque development
The apolipoprotein E-deficient mouse develops spontaneous atherosclerotic plaque
Sites of atherosclerotic plaque in apolipoprotein E-deficient mice
Nakashima et al Arterioscler Thromb )14: 133 )1994
Aortic arch and atherosclerotic plaque • The aortic arch is a major site for the development of atherosclerotic plaque • Progressive changes in plaque development were followed for up to 17 months in apoE-deficient mice • Epon-embedded sections were stained with alkaline toluidine blue
Dissected aortic arch Left
Right
mm
Aortic arch sampling
Ni et al J Nutr 128:1884-9 ))1994
Aortic arch sampling
Macrophages have complex roles in developing plaque
)Hajjar & Nicholson Am Sci 83:459-467 )1995
Osmium-stained lipid in macrophages inTunica intima
Macrophages inT.intima
Macrophages inT.intima
Macrophages form lipid pools
?Macrophage escape
Macrophages
Ultrastructure of intimal macrophage
Early fatty streak
Fatty streak
Early fatty streak
Advanced fatty streak
Advanced fatty streak
Elastic membranes ofT.media rupture
Smooth muscle changes in the T. media
Smooth muscle changes in theT. media
Invasion of theT.adventitia
Lipid pools and cholesterol
Lipid pools can be large
Fibrous cap and lipid pools
Cholesterol
Cholesterol
Cholesterol and lipid pools
Cholesterol
Cholesterol
Cholesterol
Cholesterol
Precalcification
Cartilage-like cells and precalcification
Early calcification
Calcification
Calcification
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Plaque lesion size in aortic arch of apolipoprotein Edeficient mice according to age Cumulative data from our studies over a 10 year period
square micrometers
350000 300000 250000 200000 150000 100000 50000 0 6 8 10 12 14 16 20 24 32 44 weeks
Plaque progression in apoEdeficient mice )Meir KS, Leitersdorf E ATVB 24:1007 )2004
Plaque development
)Navab et al Am J Cardiol 76:18C-23C )1995
Monocytes adhere to endothelium as precursors of intimal macrophages
Plaque development
)Navab et al Am J Cardiol 76:18C-23C )1995
Plaque development
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
Plaque development: hemodynamic forces, monocytes and adhesion molecules
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
Complex roles of macrophages
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
LDL oxidation and antioxidants
)Schwerke DC J Nutr Biochem 9: 424-445 )1998
Cholesterol synthesis
iNOS Immunohistochemical localization in aortic arch
6 WEEKS
10 WEEKS
8 WEEKS
12 WEEKS
VEGF Immunohistochemical localization in aortic arch
6 WEEKS
10 WEEKS
8 WEEKS
12 WEEKS
MMP 2 Immunohistochemical localization in aortic arch
6 WEEKS
10 WEEKS
8 WEEKS
12 WEEKS
iNOS The iNOS expression increases over time, suggesting that iNOS accelerates lesion progression from an early time point and that the .amount of iNOS-mediated injury increases over time VEGF VEGF immunostaining shows a time-dependent increase in VEGF expression; in early steps )6-8 weeks). The positivity is present mainly in theTunica intima layer near the injury site. At 10-12 weeks we observe a spread of immunostaining also in theTunica media .layer MMP2 MMP2 immunostaining shows a similar pattern of MMP2 expression at .all times studied
The problem of unstable plaque • Most heart attacks occur when an area of unstable plaque ruptures and breaks away • This causes a blood clot and subsequent abrupt flow blockage • This may occur in areas of arteries where plaque was not obstructing the artery • Unstable plaque is far more dangerous than stable )fibrous cap) plaque
The problem of plaque
Unstable plaque
Stable plaque
Unstable plaque
Unstable plaque
Unstable plaque
Unstable plaque rupture
Tissue factor in thrombus formation )ATVB 24: )2004
Plaque rupture
Plaque rupture
)Navab et al. Am J Cardiol 76: 18C-23C )1995
Plaque rupture
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
Unstable plaque
?How to reduce risk of plaque rupture Increase stability by: • Decreasing lipid core • Decreasing vascular wall inflammation • Strengthening the fibrous cap
Reduce risk factors by: • Decreasing mechanical stress • Decreasing blood pressure • Decreasing cardiac rate
Mindguard “diverter” for unstable plaque
Lipoproteins: the good, the bad and the ugly
Damage control
Plaque retardation? Exercise, healthy diet, cholesterol-reducing drugs
?Jogging
?Statins for everybody
Damage control
Functional Imaging of Plaque )RP Choudhury et al. Nature Reviews 3:913-925 )2004
Coronary arteries in apolipoprotein E-deficient mice • Apolipoprotein E-deficient mice with extensive atherosclerotic plaques in the aorta, surprisingly, do not show any pathological changes in their coronary arteries • Lack of histopathological changes in coronary arteries in hypercholesterolemic mice means these are not a suitable model to study coronary disease
Coronary arteries in hypercholesteremic apolipoprotein E-deficient mice remain plaque-free
Conclusions • Animals, unlike humans, do not suffer from heart attacks (infarcts) and rarely develop spontaneous atherosclerosis • The apolipoprotein E-deficient mouse model has proved to be the best and most rewarding animal research model for the study of hypercholesterolemia, atherosclerosis and to test the efficacy of drug intervention and therapy
Take home message
”Prevention is better than cure“
Take home message
”An apple a day keeps the doctor away“ Old English proverb
Macrophages and Atherosclerosis
Histopathology of atherosclerosis Raymond Coleman, Tony Hayek, Shlomo Keidar & Michael Aviram Rappaport Faculty of Medicine Haifa, Israel
Cardiovascular disease: the major cause of premature mortality
Coronary blockage
Risk factors for atherosclerosis • • • • • • • • • • • • • • •
Genetic (inherited) Gender (maleness) Intimal injury Vascular hemodynamics (shear stress) Hypertension Inflammation Infection (Chlamydia) and immune responses (?) Lipid disorders (hypercholesterolemia) Diabetes Cigarette smoking Elevated homocysteine Elevated iron Elevated C reactive protein Lifestyle (sedentary, eating disorders, Western diet) Cardiovascular aging changes
Risk factors? More than you imagine
Hypercholesterolemia is widely regarded as a major risk factor for atherosclerosis
Clinton’s diet
Apolipoprotein E-deficient mice • Since the early 1990s the apolipoprotein Edeficient mouse has provided a useful animal model of hypercholesterolemia and the progressive development of atherosclerotic plaque similar to that of humans • The earliest stages of plaque development are seen within 6-8 weeks • Quantitative image analysis of plaque permits research on the effectiveness of drugs or food additives in retarding plaque development
The apolipoprotein E-deficient mouse develops spontaneous atherosclerotic plaque
Sites of atherosclerotic plaque in apolipoprotein E-deficient mice
Nakashima et al Arterioscler Thromb )14: 133 )1994
Aortic arch and atherosclerotic plaque • The aortic arch is a major site for the development of atherosclerotic plaque • Progressive changes in plaque development were followed for up to 17 months in apoE-deficient mice • Epon-embedded sections were stained with alkaline toluidine blue
Dissected aortic arch Left
Right
mm
Aortic arch sampling
Ni et al J Nutr 128:1884-9 ))1994
Aortic arch sampling
Macrophages have complex roles in developing plaque
)Hajjar & Nicholson Am Sci 83:459-467 )1995
Osmium-stained lipid in macrophages inTunica intima
Macrophages inT.intima
Macrophages inT.intima
Macrophages form lipid pools
?Macrophage escape
Macrophages
Ultrastructure of intimal macrophage
Early fatty streak
Fatty streak
Early fatty streak
Advanced fatty streak
Advanced fatty streak
Elastic membranes ofT.media rupture
Smooth muscle changes in the T. media
Smooth muscle changes in theT. media
Invasion of theT.adventitia
Lipid pools and cholesterol
Lipid pools can be large
Fibrous cap and lipid pools
Cholesterol
Cholesterol
Cholesterol and lipid pools
Cholesterol
Cholesterol
Cholesterol
Cholesterol
Precalcification
Cartilage-like cells and precalcification
Early calcification
Calcification
Calcification
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Occlusion of the lumen
Plaque lesion size in aortic arch of apolipoprotein Edeficient mice according to age Cumulative data from our studies over a 10 year period
square micrometers
350000 300000 250000 200000 150000 100000 50000 0 6 8 10 12 14 16 20 24 32 44 weeks
Plaque progression in apoEdeficient mice )Meir KS, Leitersdorf E ATVB 24:1007 )2004
Plaque development
)Navab et al Am J Cardiol 76:18C-23C )1995
Monocytes adhere to endothelium as precursors of intimal macrophages
Plaque development
)Navab et al Am J Cardiol 76:18C-23C )1995
Plaque development
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
Plaque development: hemodynamic forces, monocytes and adhesion molecules
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
Complex roles of macrophages
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
LDL oxidation and antioxidants
)Schwerke DC J Nutr Biochem 9: 424-445 )1998
Cholesterol synthesis
iNOS Immunohistochemical localization in aortic arch
6 WEEKS
10 WEEKS
8 WEEKS
12 WEEKS
VEGF Immunohistochemical localization in aortic arch
6 WEEKS
10 WEEKS
8 WEEKS
12 WEEKS
MMP 2 Immunohistochemical localization in aortic arch
6 WEEKS
10 WEEKS
8 WEEKS
12 WEEKS
iNOS The iNOS expression increases over time, suggesting that iNOS accelerates lesion progression from an early time point and that the .amount of iNOS-mediated injury increases over time VEGF VEGF immunostaining shows a time-dependent increase in VEGF expression; in early steps )6-8 weeks). The positivity is present mainly in theTunica intima layer near the injury site. At 10-12 weeks we observe a spread of immunostaining also in theTunica media .layer MMP2 MMP2 immunostaining shows a similar pattern of MMP2 expression at .all times studied
The problem of unstable plaque • Most heart attacks occur when an area of unstable plaque ruptures and breaks away • This causes a blood clot and subsequent abrupt flow blockage • This may occur in areas of arteries where plaque was not obstructing the artery • Unstable plaque is far more dangerous than stable )fibrous cap) plaque
The problem of plaque
Unstable plaque
Stable plaque
Unstable plaque
Unstable plaque
Unstable plaque
Unstable plaque rupture
Tissue factor in thrombus formation )ATVB 24: )2004
Plaque rupture
Plaque rupture
)Navab et al. Am J Cardiol 76: 18C-23C )1995
Plaque rupture
)Hajjar & Nicholson Am Sci 83: 459-467 )1995
Unstable plaque
?How to reduce risk of plaque rupture Increase stability by: • Decreasing lipid core • Decreasing vascular wall inflammation • Strengthening the fibrous cap
Reduce risk factors by: • Decreasing mechanical stress • Decreasing blood pressure • Decreasing cardiac rate
Mindguard “diverter” for unstable plaque
Lipoproteins: the good, the bad and the ugly
Damage control
Plaque retardation? Exercise, healthy diet, cholesterol-reducing drugs
?Jogging
?Statins for everybody
Damage control
Functional Imaging of Plaque )RP Choudhury et al. Nature Reviews 3:913-925 )2004
Coronary arteries in apolipoprotein E-deficient mice • Apolipoprotein E-deficient mice with extensive atherosclerotic plaques in the aorta, surprisingly, do not show any pathological changes in their coronary arteries • Lack of histopathological changes in coronary arteries in hypercholesterolemic mice means these are not a suitable model to study coronary disease
Coronary arteries in hypercholesteremic apolipoprotein E-deficient mice remain plaque-free
Conclusions • Animals, unlike humans, do not suffer from heart attacks (infarcts) and rarely develop spontaneous atherosclerosis • The apolipoprotein E-deficient mouse model has proved to be the best and most rewarding animal research model for the study of hypercholesterolemia, atherosclerosis and to test the efficacy of drug intervention and therapy
Take home message
”Prevention is better than cure“
Take home message
”An apple a day keeps the doctor away“ Old English proverb
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