It’s ALIVE: It’s ALIVE: Atherogenesis, a Atherogenesis, a

Dynamic Inflammatory Dynamic Inflammatory ProcessProcess

Kathy Robinson, PhD, RN, CCNSKathy Robinson, PhD, RN, CCNSUniversity of North FloridaUniversity of North Florida

School of NursingSchool of NursingNTI, New Orleans, May, 2005NTI, New Orleans, May, 2005

www.culligan.com

RN Magazine

Concepts to RememberConcepts to Remember

Inflammatory/Immune responseInflammatory/Immune response EndotheliumEndothelium CytokinesCytokines Functions of “Good” CholesterolFunctions of “Good” Cholesterol Renin Angiotensin Aldosterone Renin Angiotensin Aldosterone

System (RAAS)System (RAAS)

INFLAMMATORY/IMMUNE INFLAMMATORY/IMMUNE RESPONSESRESPONSES

Inflammatory response:Inflammatory response:– GeneralizedGeneralized– Can be triggered by:Can be triggered by:

Microbial invadersMicrobial invaders Mechanical stressMechanical stress Chemical stressChemical stress Oxidative stressOxidative stress OtherOther

Inflammatory ResponseInflammatory Response

Four Basic PhenomenaFour Basic Phenomena– Changes in vascular tone of blood Changes in vascular tone of blood

vesselsvessels– Increased oxygen utilization by cells Increased oxygen utilization by cells

facilitating the responsefacilitating the response– Changes in blood vessel walls (short Changes in blood vessel walls (short

term: inc. capillary permeability; long term: inc. capillary permeability; long term: smooth muscle proliferation)term: smooth muscle proliferation)

– Changes in coagulation Changes in coagulation

Origination of Free Radicals/ Origination of Free Radicals/ ROSROS

absorption of extreme energy absorption of extreme energy sourcessources– ultraviolet lightultraviolet light– x-raysx-rays– Star Trek PhaserStar Trek Phaser

Endogenous (oxidative) reactionsEndogenous (oxidative) reactions Enzymatic metabolism of Enzymatic metabolism of

exogenous chemical or drugsexogenous chemical or drugs

Oxidative StressOxidative Stress

McCance & Heuther, Mosby Co.

Immune ResponseImmune Response

Much more specific than the Much more specific than the inflammatory responseinflammatory response

Involves memory and specificityInvolves memory and specificity Antigen/Antibody responseAntigen/Antibody response Can sustain inflammatory responseCan sustain inflammatory response

EndotheliumEndothelium

More than a plasma barrierMore than a plasma barrier Produces:Produces:

– Vasoconstrictors (endothelin [Et-1]) and Vasoconstrictors (endothelin [Et-1]) and vasodilators (nitric oxide [NO], vasodilators (nitric oxide [NO], prostacyclin [PGIprostacyclin [PGI22] )] )

– Pro-thrombotic, anti-thrombotic and Pro-thrombotic, anti-thrombotic and fibrinolytic substancesfibrinolytic substances

– Adhesion molecules (platelets, Adhesion molecules (platelets, monocytes, lymphocytes)monocytes, lymphocytes)

vv

Key PointKey Point

All atherogenesis is related to an All atherogenesis is related to an inflammatory response to endothelial inflammatory response to endothelial

damagedamage

CytokineCytokine

““Any of several regulatory proteins, Any of several regulatory proteins, such as the interleukins and such as the interleukins and lymphokines, that are released by lymphokines, that are released by cells of the immune system and act cells of the immune system and act as intercellular mediators in the as intercellular mediators in the generation of an immune response.”generation of an immune response.”

http://www.answers.com/topic/cytokine

BradykininBradykinin

bradykininbradykinin - - : : bradykinin \bradykinin \bra`dy*ki"nin\ n. a hypotensive bra`dy*ki"nin\ n. a hypotensive tissue hormone which acts on tissue hormone which acts on smooth muscle, dilates peripheral smooth muscle, dilates peripheral vessels and increases capillary vessels and increases capillary permeability. It is formed locally in permeability. It is formed locally in injured tissue and is believed to play injured tissue and is believed to play a role in the inflammatory process. a role in the inflammatory process.

Collaborative International Dictionary of English Collaborative International Dictionary of English v.0.48v.0.48

TNFTNF

Tumor Necrosis FactorTumor Necrosis Factor– One of a family of cytokines that has One of a family of cytokines that has

both anti-neoplastic and pro-both anti-neoplastic and pro-inflammatory effects.inflammatory effects.

The Renin Angiotensin Aldosterone The Renin Angiotensin Aldosterone System (RAAS)System (RAAS)

http://academic.pgcc.edu/

© The University of Florida

http://medinfo.ufl.edu/cme/grounds/cv/gibbons/slide21.html

Pro-Inflammatory Effects of Pro-Inflammatory Effects of Angiotensin IIAngiotensin II

Production of ROSProduction of ROS Production of CytokinesProduction of Cytokines Adhesion moleculesAdhesion molecules

Sources of Angiotensin IISources of Angiotensin II

Conversion of Angiotensin I to Conversion of Angiotensin I to Angiotensin II via ACEAngiotensin II via ACE

Up to 50% of all Angiotensin II is Up to 50% of all Angiotensin II is produced in the tissue, independent produced in the tissue, independent of the ACE pathway.of the ACE pathway.

Function of “Good” CholesterolFunction of “Good” Cholesterol

www.ha.org.hk/org/ antitb/images/hdl.gif

Other than Transport…..Other than Transport…..

Anti-inflammatoryAnti-inflammatory Anti-oxidativeAnti-oxidative Anti-aggregatoryAnti-aggregatory Anti-coagulantAnti-coagulant Pro-fibrinolyticPro-fibrinolytic

Jerzy-Roch Nofer, et al. (2001)Jerzy-Roch Nofer, et al. (2001)

Other than Transport…..Other than Transport…..

HDL Inhibits:HDL Inhibits:– Chemotaxis of monocytesChemotaxis of monocytes– Adhesion of leukocytesAdhesion of leukocytes– Endothelial dysfunctionEndothelial dysfunction– ApoptosisApoptosis– LDL OxidationLDL Oxidation– Complement activationComplement activation– Platelet activationPlatelet activation– Factor X activationFactor X activation

Other than Transport……Other than Transport……

HDL promotesHDL promotes– Endothelial cell repair/regenerationEndothelial cell repair/regeneration– Smooth muscle proliferationSmooth muscle proliferation– Synthesis of prostacyclinSynthesis of prostacyclin– Synthesis of naturietic peptideSynthesis of naturietic peptide– Activation of Protein C and Protein SActivation of Protein C and Protein S

The Basic Process of The Basic Process of Atheroma FormationAtheroma Formation

A Vicious Cycle is Born!!A Vicious Cycle is Born!!

ATHEROSCLEROSIS

ENDOTHELIALDISRUPTION

INFLAMMATION

KEY POINTKEY POINT

Atherogenesis is the result of AND Atherogenesis is the result of AND results in sustained chronic results in sustained chronic

inflammationinflammation

Treatment StrategiesTreatment Strategies AspirinAspirin

– Anti-inflammatory effects even at low dosesAnti-inflammatory effects even at low doses– Anti-platelet activityAnti-platelet activity

ACE Inhibitors/ARBsACE Inhibitors/ARBs– ACE Inhibitors block conversion of Angiotensin I to ACE Inhibitors block conversion of Angiotensin I to

Angiotensin II; also interferes with bradykinin productionAngiotensin II; also interferes with bradykinin production– ARBs block effects of Angiotensin II at receptor sites; ARBs block effects of Angiotensin II at receptor sites;

preserves bradykinin functionpreserves bradykinin function CarvedilolCarvedilol

– Suppresses inflammatory cytokinesSuppresses inflammatory cytokines– Anti-oxidantAnti-oxidant

Aldosterone blockadeAldosterone blockade

Treatment StrategiesTreatment Strategies

Drug eluting Drug eluting stents:stents:– Slowly releases Slowly releases

sirolimus sirolimus – Drug absorbed by Drug absorbed by

arterial wallarterial wall– Prevents endothelial Prevents endothelial

proliferationproliferation Next Generation:Next Generation:

– Drugs to enhance Drugs to enhance endothelial repairendothelial repair www.ptca.org

PULLING IT ALL PULLING IT ALL TOGETHERTOGETHER

Insults to EndotheliumInsults to Endothelium

AGEs: Advanced glycosylation AGEs: Advanced glycosylation endproductsendproducts

Reactive Oxygen SpeciesReactive Oxygen Species HyperinsulinemiaHyperinsulinemia HypertensionHypertension HomocysteineHomocysteine Activated T-Cells/LymphocytesActivated T-Cells/Lymphocytes Small dense LDLSmall dense LDL

Relationship to Risk Relationship to Risk FactorsFactors

Central AdiposityCentral Adiposity

SmokingSmoking

Causes intimal injuryCauses intimal injury Promotes oxidationPromotes oxidation Promotes inflammatory response in Promotes inflammatory response in

respiratory tractrespiratory tract Enhances platelet aggregationEnhances platelet aggregation Promotes vasoconstrictionPromotes vasoconstriction

Diabetes MellitusDiabetes Mellitus

Production of AGEsProduction of AGEs Hyperglycemia induces inflammatory Hyperglycemia induces inflammatory

responseresponse Frequently co-exists with small dense Frequently co-exists with small dense

LDLLDL Insulin growth factor promotes Insulin growth factor promotes

smooth muscle proliferationsmooth muscle proliferation

Hypertension Obesity Hyper-insulinemia

DiabetesHypertri-

glyceridemiaSmall,

dense LDLLow HDL Hypercoagu-

lability

Atherosclerosis

Insulin Resistance

Interrelation Between Atherosclerosis Interrelation Between Atherosclerosis

and Insulin Resistanceand Insulin Resistance

Chronic InfectionChronic Infection

How is chronic infection relation to How is chronic infection relation to atherogenesis?atherogenesis?

Possible Agents:Possible Agents:– Peridontal diseasePeridontal disease– Chlamydia pneumoniaeChlamydia pneumoniae– Helicobacter pyloriHelicobacter pylori– Herpes simplex virusHerpes simplex virus– CytomegalovirusCytomegalovirus

Inflammatory MarkersInflammatory Markers

Homocysteine levelsHomocysteine levels IL6IL6 Chlamydia titersChlamydia titers Serum amyloidsSerum amyloids CRPCRP

Future Treatment StrategiesFuture Treatment Strategies

Genomic therapyGenomic therapy Synthetic HDLSynthetic HDL Antibiotics?Antibiotics? Renin/Aldosterone BlockadeRenin/Aldosterone Blockade pFOX (partial fatty oxidation)pFOX (partial fatty oxidation)

This presentation will be available at This presentation will be available at http://www.unf.edu/~krobinso/nti.hthttp://www.unf.edu/~krobinso/nti.html from May 16ml from May 16, 2005 until June 1, 2005., 2005 until June 1, 2005.