disease, studies at the cellular and molecular level

Cardiovascular disease, studies at the cellular and molecular level

Linda Lowe‐Krentz

Bioscience in the 21st CenturyBioscience in the 21 Century

October 4, 2010

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

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

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

• 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”

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

Chart 2-2. Prevalence of CVDs in adults age 20 and older by age and sex. (1999-2004)

65.2

74.4



http://circ.ahajournals.org/cgi/content/full/119/3/e21/FIG2191262

Chart 2-2. Prevalence of CVDs in adults age 20 and older by age and sex. (1999-2004)

65.2

74.4



http://circ.ahajournals.org/cgi/content/full/119/3/e21/FIG2191262

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.

Chart 3-6. Ten year risk for CHD by risk factors

Statins


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


Diabetes No No Yes Yes

Cigarettes No No No Yes

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.

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

Progression of Vascular DiseaseProgression of Vascular Disease

Statins

Stent

Statins

Aspirin

MedlinePlus Medical Encyclopedia

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

MedlinePlus Medical Encyclopedia

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.

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

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

• 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

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

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

Identifying possible markersIdentifying possible markers

GC-MS

Picture from Wikipedia

Cell proliferation and wound repairCell proliferation and wound repair• Lack of contact, damaging chemicals, etc.

• Growth factors, Angiotensin

• Immune systemy

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

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

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

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disease, studies at the cellular and molecular level