disease, studies at the cellular and molecular level
TRANSCRIPT
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Cardiovascular disease, studies at the cellular and molecular level
Linda Lowe‐Krentz
Bioscience in the 21st CenturyBioscience in the 21 Century
October 4, 2010
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ContentContent• Introduction – The number 1 killer in America
Some statistics– Some statistics
– Recommendations
Th di• The disease process– Damage
– Current treatments
• Control of vascular tone
• Investigating the system– MetabolomicsMetabolomics
– Protein investigations
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Risk FactorsRisk Factors
• High blood pressure (above 120/80 mm Hg)High blood pressure (above 120/80 mm Hg)
• High cholesterol [aim for below 100 mg/dLLDL cholesterol and above 50 mg/dL HDL orLDL cholesterol and above 50 mg/dL HDL, or aim for total cholesterol below 200 mg/dL]
Hi h B d M I d (BMI) [ b 30]• High Body Mass Index (BMI) [above 30]
• Smoking
• Drinking
• DiabetesDiabetes
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Metabolic Syndromey• Central obesity (excessive fat tissue in and around the abdomen)the abdomen)
• Atherogenic dyslipidemia (blood fat disorders —mainly high triglycerides and low HDL cholesterol)mainly high triglycerides and low HDL cholesterol)
• Insulin resistance or glucose intolerance (the body can’t properly use insulin or blood sugar)can t properly use insulin or blood sugar)
• Pro‐thrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood)plasminogen activator inhibitor in the blood)
• Raised blood pressure (130/85 mmHg or higher)
• Pro‐inflammatory statePro inflammatory state
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• Diet • Fat as an endocrine tissueDiet
• Portion size
• Physical Activity
Fat as an endocrine tissue– Makes leptin – lowered desire to eat, more use of
Physical Activity
• Genesstored fat
– Makes inflammatory signaling moleculessignaling molecules
– Decreases synthesis of signals that in turn cause a decrease in blood pressure – with the result being increased blood pressurep
Ob/ob mouse from “Nutritional Science”
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Chart 2-1 Trends in the age-adjusted prevalence of health conditionsUS adults ages 20 to 74
Rosamond, W. et al. Circulation 2007;115:e69-e171
Copyright ©2007 American Heart Association
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Chart 2-2. Prevalence of CVDs in adults age 20 and older by age and sex. (1999-2004)
65.2
74.4
Rosamond, W. et al. Circulation 2007;115:e69-e171
Copyright ©2007 American Heart Association
http://circ.ahajournals.org/cgi/content/full/119/3/e21/FIG2191262
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Chart 2-2. Prevalence of CVDs in adults age 20 and older by age and sex. (1999-2004)
65.2
74.4
Rosamond, W. et al. Circulation 2007;115:e69-e171
Copyright ©2007 American Heart Association
http://circ.ahajournals.org/cgi/content/full/119/3/e21/FIG2191262
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140 9
200
tion
60 7
110.0
140.9
100
150
000
Popu
la
44.0 41.523.4
60.740.0 32.8
0
50
Per 1
00,0
0Coronary Heart
DiseaseStroke Lung Cancer Breast Cancer
Whit F l Bl k F l
AgeAge--adjusted death rates for CHD stroke lung and breastadjusted death rates for CHD stroke lung and breast
White Females Black Females
9
AgeAge adjusted death rates for CHD, stroke, lung and breast adjusted death rates for CHD, stroke, lung and breast cancer for white and black femalescancer for white and black females (United States: 2005).(United States: 2005).Source: NCHS and NHLBI.Source: NCHS and NHLBI.
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Chart 3-6. Ten year risk for CHD by risk factors
Statins
Rosamond, W. et al. Circulation 2007;115:e69-e171
A B C DA B C D
BP, mm HG 120/ 80
140/ 90
140/ 90
140/ 90
mg/dL Total 200 240 240 240mg/dL, Total Cholesterol
200 240 240 240
Mg/dL HDL cholesterol
50 50 40 40
Copyright ©2007 American Heart Association
Diabetes No No Yes Yes
Cigarettes No No No Yes
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218 4
313.8
Digestive System 520-579
Cardiovascular 340-459
166 8
172
172.5
218.4
Injury and Poisoning 800 999
Nervous System 320-389
Mental 290-319
Digestive System 520 579
122.3
155.3
166.8
Musculoskeletal system 710-739
Respiratory System 460-519
Injury and Poisoning 800-999
85
99
91.1
Endocrine System 240-279
Genitourinary System 580-629
Neoplasms 140-239
Di t C tDi t C t (Billi f d ll ) f(Billi f d ll ) f th 10 L dith 10 L di
0 50 100 150 200 250 300 350
11
Direct Costs Direct Costs (Billions of dollars) of (Billions of dollars) of the 10 Leading the 10 Leading Diagnostic Groups Diagnostic Groups ((United States: 2009)United States: 2009). . Source: NHLBI. Source: NHLBI.
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Recommendations• Limit your saturated fat intake (trans fat too)• Consume less than 200 (300) mg/day cholesterolConsume less than 200 (300) mg/day cholesterol• Eat fish regularly• Limit your salt intake (less than 2300 mg/day)y ( g/ y)• Consume vegetables and whole grains• Diet options for lowering cholesterol
• Plant sterols and/or soluble fiber
• Eat only enough calories to maintain weight (or reach a healthy weight)reach a healthy weight)
• At least 30 min of moderate physical activity/day• http://www.americanheart.org/presenter.jhtml?http://www.americanheart.org/presenter.jhtml?identifier=851
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Progression of Vascular DiseaseProgression of Vascular Disease
Statins
Stent
Statins
Aspirin
MedlinePlus Medical Encyclopedia
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Atherosclerosis
Leads to narrowing/ blocking of arteries g Blocked flow to the heart Myocardial Infarction y(heart attack)
Blocked flow to the brain Ischemic Stroke
Bypass
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MedlinePlus Medical Encyclopedia
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Atherosclerosis is Geometrically Focal
Disturbed Flow Region
“Sticky” ECs
Smooth Flow Region
Sticky ECs“Non-Sticky” ECs
“L k ”Intact Endothelium Inflammed “Leaky”
EndotheliumEndothelium Inflammed
vasculatureMeron Mengistu
Flow, along with other factors, contributes to risk.
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Contraction of blood vesselsContraction of blood vessels
• Angiotensin is a major contraction signal thatAngiotensin is a major contraction signal that increases blood pressure transiently
DiureticsDiuretics,Ace inhibitors, β blockers
ANG IIβ‐blockers,Calcium channel bl kblockers
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Relaxation of blood vesselsRelaxation of blood vessels
• NO (nitric oxide) and atrial natriuretic factorNO (nitric oxide) and atrial natriuretic factor both cause increases in cGMP
cGMPNitroglycerin
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• But cGMP is typically rapidly degraded by• But cGMP is typically rapidly degraded by proteins called PDEs
• PDE3 is primarily in cardiac muscle
• PDE6 is primarily in the retinasPDE6 is primarily in the retinas
• PDE5 is primarily in vascular smooth lmuscle
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Sildenafil citrateSildenafil citrate
• Blocks PDE5 80 to 4000 times more effectivelyBlocks PDE5 80 to 4000 times more effectively than it blocks other PDE isoforms (except PDE6)PDE6)
• Therefore in vascular smooth muscle cells cGMP remains elevated longercGMP remains elevated longer.
• Viagra is a trade name for sildenafil citrate
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Statins and complications?Statins and complications?• Some individuals do not tolerate statins well, and they sometimes develop myopathy.
• How can we detect this early?y
• Searching for a marker.
• “omics”• omics– Genomics (transcriptomics)
P t i– Proteomics
– MetabolomicsE i i t b li d t d/ i t di t• Examining metabolic products and/or intermediates
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Identifying possible markersIdentifying possible markers
GC-MS
Picture from Wikipedia
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Cell proliferation and wound repairCell proliferation and wound repair• Lack of contact, damaging chemicals, etc.
• Growth factors, Angiotensin
• Immune systemy
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Finding a player (protein)Finding a player (protein)The human genome has only about 23,000 protein encodingprotein-encoding genes; it seems like the search should be possible, if not easy.
http://www.bordalierinstitute.com/target1.html
http://www.estradalab.org/research/index.html
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Finding a player (protein)Finding a player (protein)
Matrix-assisted laser desorption/ionization Mass Spectrometry, a technique sometimes used to characterize and/or identify proteinsproteins
http://www.psrc.usm.edu/mauritz/maldi.htmlhttp://www.pharmaceutical-technology.com/contractors/imaging-analysis/anagnostec/anagnostec2.html
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What can you know about theWhat can you know about the protein you identify?
• Sequence of the protein – gene sourceAGACYSSTRKGQN…..
Sequence of the protein gene source
• Location
• Structure
• Function
• Amounts present