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Vascular Biology of Diabetes

Vascular Biology of Diabetes. Abdel Moniem Ibrahim Ahmed, MD Professor of Cardiovascular Physiology Cairo University Oct . 15 . 2003. Diabetes is a Cardiovascular disease. The concept of Endothelial Dysfunction (ED). Mechanisms of ED in diabetes:-

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Vascular Biology of Diabetes

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  1. Vascular Biology of Diabetes Abdel Moniem Ibrahim Ahmed, MD Professor of Cardiovascular Physiology Cairo University Oct . 15 . 2003

  2. 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 .

  3. 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 .

  4. Independent major risk factor Accelerated atherosclerosis Diabetes Mellitus morbidity & mortality (80 %) Cardiovascular Diseases

  5. Normal Volunteers Acute Hyperglycemia Rapid BP elevation Glucose levels trigger functional alterations in vasomotor motions Marfella et al . Am J Physiol Endocrinol Metab . 1995 , 268 : E 1167 -

  6. Diabetic Microangiopathy At later stages At early stage • Irrevesible changes : • Thickening of the basement membrane • Extracellular accumulation of proteins • Reversible changes : • Capillary press . • Blood flow . • EC permeability . Arosio et al . Ann Ital Med Int . 1999 ; 14 (2) : 106-

  7. The onset of microvascular lesions in diabetes has been preceded by 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

  8. In diabetic patients E N D O T H E L I U M The primary target of unbalanced glycemic control. Involved in the pathogenesis of vascular complications. Pomilio et al . I pediatr Endocrinol Metab .2002 ; 15(4): 343-

  9. Endothelial pathophysiologic balance • 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 • Vasodilators • Nitric 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

  10. 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 .

  11. HyperglycemiaAdvanced Glycosylation End Products Oxidized Lipoproteins Insulin Resistance INCREASED PROTHROMBOTIC ACTIVITY Leukocyte adhesion molecules & chemoattractants Cell surface procoagulant activity Altered junctions & transport EDRF PGI2 Expression of growth factors & mitogens INCREASED PERMEABILITY & TRAPPING of LDL IMPAIRED VASORELAXATION (VASOSPASM) INCREASED LEUKOCYTE RECRUITMENT SMC MIGRATION, PROLIFERATION & ECM PRODUCTION

  12. “ 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.

  13. Endothelial Nitric Oxide Production GTP VSMc c GMP SM relaxation (+) Guanylyl cyclase TARGET CELLS (SMC, EC, PLATELETS) [NO/EDRF] LSS Growth Factors LSS Acetylcholine (other mediators) L-arg [Ca+2, IP3] ecNOS ecNOS L-arginine citrulline ACUTE CHRONIC

  14. 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 .

  15. Proposal consequence ( transient & cumulative) of hyperglycmic episodes on vascular wall . Goligorsky et al . Hypertension .2001; 37 [part2] : 744

  16. “ The ED initiation events is linked to scavenging of NO by glucose ( NO bioavailability ) during transient episodes of hyperglycemia ”

  17. (-) Vasorelaxation 15 min. after hyperglycemia Acute Hypertensive response NO Bioavailability (+) Platelet reactions prothrmbotic activity (+) (MN) leukocyte chemotaxis & activation (+) Express . of leukocyte - CAMs (+) VSMC migration & proliferation Acceleration of Atherosclerosis Brodsky et al . Am J Physiol Renal Physiol . 2001; 280: F 480-

  18. NO scavenging (Chronic)

  19. 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 .

  20. In healthy subjects (+) Acute Hyperglycemia Mitochondrial superoxide (O2.-) production ROS+ NO Peroxynitrites (ineffective) Plasma nitrotyrosine (marker of oxid . Stress ) NO Bioavailability Marfella et al . JCI . 2001 , 108 (4) : 635

  21. Hyperglycemia in Diabetes Tissue deposition Hyperglycemia in Diabetes Aging Non-enzymatic reaction Primary amino acid groups on protein Ambient glucose Maillard reaction Amadoric products Dehydration Fragmentation AGEs in the Sub-EC Compartment Friedman . Nephrol Dial Transport . 1999; 14 [Suppl 3] : 1-9

  22. NO Bioavailability Bind with their receptors RAGE (EC, VSMC, Macrophages) AGEs Quench NO activity ROS Tan et al . Diabetic Care . 2002; 25 (6): 1055

  23. AGE - RAGE interaction is a potential source for cell-mediatedoxidation & lipid peroxidation

  24. Oxidative-modification hypothesis Diaz et al.NEJM.1997,337(6) : 408

  25. NO Bioavailability Glucose – induced O2.- Mitochondrial O2.-over Hyperglycemia Diacylglycerol (DAG) Protein kinase C (PKC) activation (+) NAD(P) H oxidase (-) PI3kinase- mediatedeNOS(+) ROS Beckman et al . Circ Res . 2002 ; 90 : 107-

  26. 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 .

  27. Quench NO Activity Consume EC-derived NO Functional NO deficiency AGEs Deficiency of Angiogenic response (+) fibroblast proliferation Extracellular matrix & physico-chemical changes Collagen -to- collagen cross linking & tissue rigidity Vascular Complications of Diabetes Goligorsky et al . Hypertension . 2001 ; 37 [part 2]

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

  29. (+) (+) Induction of TGF - b “chemotactic factor” AGEs VSMC migration NF- kB (+) Atherosclerosis ( ) ET-1 prod. (+) Hyperglycemia Tan et al . Diabetic care . 2002 ; 25(6) : 1055

  30. Clinical manifestations of diabetic nephropathy and potenial role of ED

  31. 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 .

  32. Cluster of Metabolic & CV Abnormalities Metabolic Syndrome Endothelium Insulin Resistance Target of Insulin’s action on vasomotility Common dominator

  33. Insulin Deleterious effects Protective effects • (-) apoptosis • (+) NO prod. • (+)VEGF . • (+) ET-1 . • Salt - sensitive HTN * Vicent et al . TCI . 2003 , III (9) : 1373- * Ogihara et al . Diabetes . 2001 , 50 : 573-

  34. (+) PKC in vascular tissues Insulin Resistance (-) PI-3 Kinase (-) eNOS express. Modulates vascular tone Kuboki et al Circulation . 2000 ; 101 : 676 -

  35. Prolonged exposure (-) EC- dependent VD Hyperinsulinemia (+) ED Vit. C O2.- (Antioxidant) (+) NAD(P) H oxidase express . (+) E T-1 Arcaro et al . Circulation . 2002 ; 105 : 576

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

  37. (+) microvascular & macrovascular complications Glycemic control (-) macrovascular & microvascular diseases Gerich . Arch Intern Med . 2003 . 9 ; 16B (11) : 1306

  38. 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 .

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