Vascular Biology Vascular Biology of Diabetesof Diabetes

Abdel Moniem Ibrahim Ahmed, MDAbdel Moniem Ibrahim Ahmed, MDProfessor of Cardiovascular Physiology

Cairo UniversityCairo University

Oct . 15 . 2003Oct . 15 . 2003

• Diabetes is a Cardiovascular disease.

• The concept of Endothelial Dysfunction (ED).

• Mechanisms of ED in diabetes:-

Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia / insulin resistance and ED .

•Diabetes is a Cardiovascular disease.

• The concept of Endothelial Dysfunction.

• Mechanisms of ED in diabetes:-

Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia / insulin resistance and ED .

Diabetes Mellitus

Independent major risk factor

Accelerated atherosclerosis

morbidity & mortality (80 %)

Cardiovascular Diseases

Acute Hyperglycemia

Normal Volunteers

Rapid BP elevation

Glucose levels trigger functional alterations in Glucose levels trigger functional alterations in vasomotor motions vasomotor motions

Marfella et al . Am J Physiol Endocrinol Metab . 1995 , 268 : E 1167 -

Diabetic Microangiopathy

At early stage

At later stages

Reversible changes :• Capillary press .• Blood flow . • EC permeability .

Irrevesible changes :• Thickening of the basement membrane • Extracellular accumulation of proteins

Arosio et al . Ann Ital Med Int . 1999 ; 14 (2) : 106-

• The onset of microvascular lesions in The onset of microvascular lesions in diabetes has been diabetes has been preceded bypreceded by endothelial dysfunction manifestations:endothelial dysfunction manifestations:

* ( ) in the vasodilatation response to vasoactive agents .

* Alterations in the antithrombotic properties.

Arosio et al . Ann Ital Med Int . 1999 ; 14 (2) : 106

In diabetic patients

ENDOTHELIUM

Pomilio et al . I pediatr Endocrinol Metab .2002 ; 15(4): 343-

The primary target of unbalanced glycemic control.

Involved in the pathogenesis of vascular complications.

Endothelial pathophysiologic balance

• Vasodilators– Nitric oxideNitric oxide– Prostacyclin– Endothelium derived

hyperpolarizing factor– C-natriuretic peptide

• Antithrombotic– Tissue type plasminogen activator– Prostacyclin– Nitric oxide

• Growth inhibitors– Nitric oxide– Prostacyclin– C-natriuretic peptide

• Inflammation inhibitors– Nitric oxide

• Vasoconstrictors– Endothelin-1– Angiotensin II– Endoperoxide (PGH2)– Thromboxane A2

• Prothrombotic– Plasminogen activator inhibitor-1– Thromboxane A2

• Growth promotors– Superoxide radicals– Endothelin– Angiotenisn II

• Inflammation promotors– Superoxide and other free radicals– Tumor necrosis factor-alpha

• Diabetes is a Cardiovascular disease.

•The concept of Endothelial Dysfunction.

• Mechanisms of ED in diabetes:-

Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia / insulin resistance and ED .

HyperglycemiaAdvanced Glycosylation End

Products Oxidized Lipoproteins

Insulin Resistance

SMC MIGRATION,PROLIFERATION&

ECM PRODUCTION

Expression ofgrowth factors&

mitogens

EDRFPGI2

Leukocyteadhesion molecules& chemoattractantsAltered

junctions &transport

Cell surfaceprocoagulant

activity

INCREASEDPROTHROMBOTIC

ACTIVITY

IMPAIRED VASORELAXATION(VASOSPASM)

INCREASEDPERMEABILITY

& TRAPPING of LDL

INCREASEDLEUKOCYTE

RECRUITMENT

“ EC - dependent vasorelaxation

( flow - mediated dilatation )by using echo Doppler has remained

the gold standard in assessing endothelial function & dysfunction .”

“ EC - dependent vasorelaxation

( flow - mediated dilatation )by using echo Doppler has remained

the gold standard in assessing endothelial function & dysfunction .”

Goligorsky et al . Hypertension .2001, 37 [part2] : 744-748.

Endothelial Nitric Oxide Production

ecNOS

ACUTE CHRONIC

L-arg

L-arginine citrullineecNOS

[Ca+2, IP3]

Acetylcholine(other

mediators)

LSS[NO/EDRF]

TARGET CELLS(SMC, EC, PLATELETS)

LSSGrowth Factors

GTP VSMc c GMP SM relaxation

(+) Guanylyl cyclase

• Diabetes is a Cardiovascular disease.

• The concept of Endothelial Dysfunction.

•Mechanisms of ED in diabetes:- Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia / insulin resistance and ED .

Proposal consequence Proposal consequence ( ( transient & cumulative) of hyperglycmic transient & cumulative) of hyperglycmic episodes on vascular wall . episodes on vascular wall .

Goligorsky et al . Hypertension .2001; 37 [part2] : 744

“ “ The ED initiation events is linked to scavenging The ED initiation events is linked to scavenging

of NO by glucose of NO by glucose ( NO bioavailability ) ( NO bioavailability ) during during

transient episodes of hyperglycemia ” transient episodes of hyperglycemia ”

Acute Hypertensive response

(-) Vasorelaxation 15 min. after hyperglycemia

NO Bioavailability

(+) Platelet reactions prothrmbotic activity(+) (MN) leukocyte chemotaxis & activation(+) Express . of leukocyte - CAMs (+) VSMC migration & proliferation

Acceleration of Atherosclerosis Acceleration of Atherosclerosis Brodsky et al . Am J Physiol Renal Physiol . 2001; 280: F 480-

NO scavenging)Chronic(

• Diabetes is a Cardiovascular disease.

• The concept of Endothelial Dysfunction.

•Mechanisms of ED in diabetes:- Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia / insulin resistance and ED .

Acute Hyperglycemia

In healthy subjects

Mitochondrial superoxide (O2.-) production

ROS + NO

Peroxynitrites (ineffective)

Plasma nitrotyrosine (marker of oxid . Stress )

(+)

Marfella et al . JCI . 2001 , 108 (4) : 635

NO Bioavailability

Aging

Non-enzymatic reaction

Ambient glucose Primary amino acid groups on protein

Maillard reaction

Amadoric products

Dehydration

Fragmentation

AGEs in the Sub-EC Compartment

Friedman . Nephrol Dial Transport . 1999; 14 [Suppl 3] : 1-9

Tissue deposition

Hyperglycemia in Diabetes

Hyperglycemia in Diabetes

AGEs

Quench NO activityBind with their receptors RAGE

(EC, VSMC, Macrophages)

ROS NO Bioavailability

Tan et al . Diabetic Care . 2002; 25 (6): 1055

AGE - RAGE interaction is a

potential source for cell-

mediated oxidation & lipid

peroxidation

AGE - RAGE interaction is a

potential source for cell-

mediated oxidation & lipid

peroxidation

Diaz et al. NEJM. 1997,337)6( : 408

Oxidative-modification hypothesisOxidative-modification hypothesisOxidative-modification hypothesisOxidative-modification hypothesis

Hyperglycemia

Glucose – induced O2

.-Mitochondrial O2

.-over

Diacylglycerol (DAG)

Protein kinase C (PKC) activation

(-) PI3 kinase- mediated eNOS(+) (+) NAD(P) H oxidase

ROS

Beckman et al . Circ Res . 2002 ; 90 : 107-

NO Bioavailability

• Diabetes is a Cardiovascular disease.

• The concept of Endothelial Dysfunction.

•Mechanisms of ED in diabetes:- Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia / insulin resistance and ED .

AGEs

Consume EC-derived NO Quench NO Activity

Extracellular matrix & physico-chemical changes

Goligorsky et al . Hypertension . 2001 ; 37 [part 2]

Functional NO deficiency

Deficiency of

Angiogenic response

(+) fibroblast proliferation

Collagen -to- collagen cross linking & tissue rigidity

Vascular Complications of Diabetes Vascular Complications of Diabetes

Proposed pathophysiological mechanisms acting during maintenance Proposed pathophysiological mechanisms acting during maintenance phase of ED . phase of ED .

Proposed pathophysiological mechanisms acting during maintenance Proposed pathophysiological mechanisms acting during maintenance phase of ED . phase of ED .

Induction of TGF - “chemotactic factor”

Hyperglycemia

VSMC migration

Atherosclerosis

Tan et al . Diabetic care . 2002 ; 25(6) : 1055

NF- B (+)

( ) ET-1 prod.

AGEs(+)

(+)

(+)

Clinical manifestations of diabetic nephropathy and potenial role of EDClinical manifestations of diabetic nephropathy and potenial role of EDClinical manifestations of diabetic nephropathy and potenial role of EDClinical manifestations of diabetic nephropathy and potenial role of ED

• Diabetes is a Cardiovascular disease.

• The concept of Endothelial Dysfunction.

• Mechanisms of ED in diabetes:-

Initiation ( trigger ) phase of ED:

(Hyperglycemia - induced ED)

Transition from initiation to maintenance phase of ED:

(Formation of AGEs)

Maintenance phase of ED:

(Tightly linked to accumulation of AGEs)

• Hyperinsulinemia/insulin resistance and ED .

Cluster of Metabolic & CV Abnormalities

Metabolic Syndrome

Insulin Resistance Endothelium

Common dominatorTarget of Insulin’s action on

vasomotility

Insulin

Protective effects Deleterious effects

• (+)VEGF .

• (+) ET-1 .

• Salt - sensitive HTN

* Vicent et al . TCI . 2003 , III (9) : 1373- * Ogihara et al . Diabetes . 2001 , 50 : 573-

• (-) apoptosis

• (+) NO prod.

Insulin Resistance

(+) PKC in vascular tissues

(-) PI-3 Kinase

(-) eNOS express.

Modulates vascular tone

Kuboki et al Circulation . 2000 ; 101 : 676 -

Hyperinsulinemia

Prolonged exposure

(-) EC- dependent VD

ED

O2.-

Vit. C

(Antioxidant)

(+) NAD(P) H oxidase express .

(+) E T-1

(+)

Arcaro et al . Circulation . 2002 ; 105 : 576

• Diabetes is a chronic vascular disease in which disordered glucose homeostasis triggers endothelial dysfunction of every organ, deriving, in part, from vascular disturbance.

• Diabetes is a chronic vascular disease in which disordered glucose homeostasis triggers endothelial dysfunction of every organ, deriving, in part, from vascular disturbance.

Conclusion

(+)(+) microvascular & macrovascular complications

Glycemic control

(-) (-) macrovascular & microvascular diseases

Gerich . Arch Intern Med . 2003 . 9 ; 16B (11) : 1306

Conclusion

• Understanding the mechanism(s) by which acute hyperglycemia induces ED in DM may lead to secondary preventive strategies to reduce CV morbidity and mortality in this highly prevalent disease .