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AGEING HEART & VESSELS Melbourne, Australia August 3-5, 2004

AGEING HEART & VESSELS Melbourne, Australia August 3-5, 2004. www.ishr.edu.au / ishr. Current Understanding, New Research and the Challenge of Reducing the Health Care Impact of Age-Related Cardiovascular Disease. Risk Factors for Cardiovascular Disease. hypertension

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AGEING HEART & VESSELS Melbourne, Australia August 3-5, 2004

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  1. AGEING HEART & VESSELS Melbourne, Australia August 3-5, 2004 www.ishr.edu.au / ishr Current Understanding, New Research and the Challenge of Reducing the Health Care Impact of Age-Related Cardiovascular Disease

  2. Risk Factors for Cardiovascular Disease • hypertension • LDL/HDL cholesterol • diabetes • family history of CAD, gender • excess alcohol, tobacco use • physical inactivity • obesity • stress • diet • advanced age

  3. Aging Involves Cardiac Remodeling With Functional Adaptation Independent of Disease • Cell enlargement • Cell rigidity • Slower electrical properties • More vulnerable to nutrient deprivation (ischemia) • More vulnerable to heart attack (arrhythmia) • Membrane protein and lipid function changed • (receptors, enzymes and signalling intermediates) • More free radical injury, less protective antioxidants • (SOD, catalase, glutathione, vit E, Coenzyme Q10...) • Less capable of hard work or recovery from stress • Cell loss (death)

  4. Consequences of Membrane Modification Qualitative changes to lipids, proteins, lipid-protein interactions - receptors, channels, enzymes, - intracellular signaling - ion homeostasis - energy metabolism - altered membrane function “efficiency” - augmented perturbation after stress & lost “reserve” Carrier, i.e., ADP Translocase Channels

  5. Diet Is a Key Factor Involved in the Reduced Incidence of Death From Age-associated Diseases From epidemiological studies of Mediterranean, Japanese, Eskimo & other populations Fish-rich (omega-3 fatty acids) versus Animal-rich (omega-6 fatty acids) Dietary Antioxidants

  6. CH CH CH 2 2 3 (CH )n 2 Polyunsaturated fatty acids, PUFA • long carbon chain (C>12, up to 24) • degree of unsaturation (double bonds) • 0= “saturated”, 1=“monounsaturated” • 2 or more = “polyunsaturated” • PUFA: increased membrane fluidity, lower melting point • omega-3 vs omega-6 : position of methyl group, • between 3 &4 vs 6 &7 • also affects fluidity and conformation • precursors of lipid peroxides and eicosanoids • signaling role  O 1 2 3 ..n.. C OH

  7. Fish or  -3 PUFA Intake Reduces Heart Disease Risk • Dart Study Lancet 1989; : 757-761 • MRFIT Proc Soc Exp Biol Med 1992; 200: 177-82 • Indian Heart Study Br Med J 1992; 304: 1015-19 • Lyon Diet Heart Study Lancet 1994; 343: 1454-9 Circulation 1999; 99: 779-85 • Health Professionals Study N Eng J Med 1995; 332: 977-82 • Primary Cardiac Arrest JAMA 1995; 274: 1363-1367 • Honolulu Heart Program Circulation 1996; 94: 952-56 • Western Electric Study N Eng J Med 1997; 336: 1046-53 • US Physicians Health Study JAMA 1998; 279: 23-28 • GISSI Prevenzione Trial Circulation 2002; 105: 1897-1903

  8. GISSI PREVENZIONE TRIAL n=5666, 850mg omega-3 PUFA, 3.5 years 100 -15% -20% 80 -45% 60 % of Patients 40 20 0 NO OMEGA-3 CV Heart Total OMEGA-3 Events Attack Mortality Marchioli R et al. , Lancet 1999 354: 457-455 Circulation 2002; 105: 1897-1903

  9. Omega-3 PUFA Attenuates the Rise in Arterial Blood Pressure due to Age or Omega-6 PUFA * 180 160 * 140 * 120 6 mo 100 24 mo Systolic Pressure(mmHg) 80 n=8 SD rats 60 40 20 0 Omega-6 PUFA Omega-3 PUFA PEPE, et al, 1999

  10. Mitochondrial Membrane PUFA  -6 PUFA -3 PUFA Age (mo)6 24 6 24 16:0 10.0±0.29 14.0±0.69* 9.5±0.35 11.0±0.64 18:0 23.0±1.15 26.0±1.73 10.1±0.72A 12.0±0.81A 16:1 0.22±0.05 0.3±0.12 0.7±0.10 0.8±0.05 18:1 9.0±0.81 9.0±0.43 9.5±0.40 10.0±0.58 18:2 ( -6) LA 17.0±1.21 11.0±1.44* 12.0±0.58A 9.0±0.69 20:4 ( -6) AA 24.0±1.44 32.0±1.79* 9.2±0.64A 12.0±0.58A 22:4 ( -6) 1.1±0.18 1.6±0.15 0.1±0.03 0.1±0.01 18:3 ( -3) 0.2±0.03 0.2±0.03 1.8±0.06 2.0±0.17 20:5 ( -3) EPA 0.1±0.03 0.1±0.05 6.0±0.17A 5.2±0.29A 22:5 ( -3) 2.0±0.12 0.8±0.12* 2.2±0.05 5.0±0.58A 22:6 ( -3) DHA 9.0±0.64 2.0±0.43* 27.0±1.01A 30.0±1.15A  -6 42.1±0.85 44.6±1.58 21.3±0.50A 1.1±0.33A  -311.3±0.69 3.1±0.44*37.1±1.1A 42.2±1.35A Values (mol/100mol) are presented as mean ±SEM, n=5. *= P<0.05 vs 6 mo; A = P<0.05 vs n-6 PUFA PEPE, et al, 1999

  11. -3 : -6 PUFA A A 2 1.5 6mo 24mo -3 : -6 PUFA 1 * 0.5 0 Omega-6 PUFA Omega-3 PUFA *=p<0.05 vs 6mo; A p<0.05 vs-6 PUFA; n=5 PEPE, et al, 1999

  12. Mitochondrial Membrane Phospholipids *=p<0.05 vs 6mo; A = p<0.05 vs -6 PUFA mean +/- SD; n=5; % of total mitochondrial phospholipids   - - 6 PUFA 3 PUFA 6 24 6 24 Age (mo) * A DPG 12±1.0 8.5±0.9 15±0.9 14±0.8 * PC 46±1.5 53±1.7 42±1.8 42±1.6 A PE 35±1.8 33±1.4 38±1.9 40±1.8 PS 2.4±0.7 2.5±0.5 2.2±0.2 2.4±0.3 PI 1.3±0.2 1.4±0.3 1.1±0.4 1.2±0.6 PEPE, et al

  13. Cardiolipin (DPG) 20 6mo 24mo A 15 * 10 % Total Phospholipids 5 0 Omega-6 PUFA Omega-3 PUFA *=p<0.05 vs 6mo; A=p<0.05 vs-6 PUFA; n=5 PEPE, et al

  14. CARDIOLIPIN Phosphatidylglycerol Unique ability to interact with proteins- physico-chemical - sensitive to oxidation Low or absent: activity of respiratory chain complexes  mitochondrial membrane potential Inner membraneIntermembrane space ADP-ATP carrier creatine kinase phosphate carrier cytochrome C pyruvate carrier carnitine carrier NADH dehydrogenase succinate dehydrogenase complex III cytochrome C oxidase ATP synthase

  15. Cardiolipin Q ANT O• O• Krebs Cycle (PDH, KGDH) The Inner Mitochondrial Membrane

  16. The Post-Ischemic Decline in Contractile Recovery is Attenuated by Omega-3 PUFA 100 I/R A A A I/R+RR 80 A * 60 * % Control PSP (Normoxia) 40 20 0 6 24 6 24 Omega-6 PUFA Omega-3 PUFA *=p<0.05 vs 6mo; A p<0.05 vs -6 PUFA; n=6 PEPE, et al, 1999

  17. Increased Omega-3 PUFA Incorporation into Cardiac Membranes Augments Cardiac Efficiency AND prevents Fatal VF Incidence of Ventricular Arrhythmia Myocardial Oxygen Consumption 100 7.5 5.0 2 (mL/min/g dry wt) normalised per unit work % Ventricular Fibrillation 50 MVO 2.5 0.0 0 omega-6 PUFA omega-3 PUFA Pepe & McLennan, 2002

  18. Mitochondrial Calcium 2.5 C 2 I/R I/R+RR 1.5 Total [Ca 2+] nmol/mg protein 1 0.5 0 6 24 6 24 Omega-3 PUFA Omega-6 PUFA PEPE, et al, 1999

  19. Pyruvate Dehydrogenase Activation 100 90 C 80 I/R I/R+RR 70 60 PDHA (% Total PDH) 50 40 30 20 10 0 6 24 6 24 Omega-6 PUFA Omega-3 PUFA PEPE, et al, 1999

  20. ADP:O Efficiency Ratio A A 2 1.5 * 6 mo 1 ADP:0 24 mo * p<0.01 vs 6mo 0.5 p<0.01 vs -6 A 0 Omega-3 PUFA Omega-6 PUFA 37C by oxidation of pyruvate (5mM)+ malate (0.5mM) during complete conversion of 0.5mM ADP to ATP PEPE, et al, 1999

  21. Summary • omega-6/ omega-3 ratio is increased with age • Cardiolipin is significantly decreased with age whereas PC is increased with age. • For the same level of contractile work, PDHA, and mito [Ca]2+ values are higher after omega-6 PUFA-rich diet and is augmented by age. • omega-3 PUFA -rich diet attenuates ALL of these effects.

  22. Conclusions • Manipulating cardiac membrane phospholipids and the omega-3/ omega -6 PUFA ratio alters the flux of Ca2+ across the mitochondrial membrane and this may markedly impact intramitochondrial Ca2+-dependent processes.

  23. Conclusions  Evidence for thermodynamic inefficiency in omega-6 PUFA or aging compared to omega-3 PUFA  Potential for Ca overload after ischemia is greater and thus more rapid onset of MPT opening and cell de-energization in omega-6 PUFA or with aging vs omega-3 PUFA .  Age-related reduction of cardiolipin augments this effect. 2+

  24. PUFA conjugated dienes lipid hydroperoxides alkoxyl radicals peroxyl radicals alkanes aldehydes (MDA 4HNE) isoprostanes hydroxylated FA 4-hydroxy-2-nonenal, 4-HNE Specific aldehydic product of oxygen free-radical induced lipid peroxidation of Omega-6 PUFAs  4-HNE -a second “toxic” messenger cytotoxic, mutagenic, genotoxic, chemotactic ROS

  25. Consequences of 4-HNE formation  Michael-addition reactions with proteins at: sulfhydryl gp of cysteine, imidazole N of histidine, -amine of lysine  Proarrhythmic changes to membrane excitability  -Activates PLC -Inhibits Na+-K+ ATPase -Inactivates glucose-6-phosphatase -Induces heat shock protein synthesis -Inactivates glutathione peroxidase (inhibits glutathione recycling) -Apolipoprotein B adducts in atherosclerosis

  26. Omega-3 PUFA Reduces Post-ischemic Coronary Release of HNE Omega-6 PUFA Omega-3 PUFA Reperfusion Time (min) PEPE, et al After 30 min global ischemia

  27. Omega-3 PUFA Reduces Post-Ischemic Mitochondrial 4-HNE Omega-6 PUFA Omega-3 PUFA PEPE, et al

  28. Conclusions  4-HNE a marker of free radical-induced peroxidation of omega-6 PUFA is increased in the post-ischemic myocardium of senescent rats vs young, due to the age-related differences in total omega-6 PUFA.

  29. Conclusions  Replacing membrane omega-6 PUFA with omega-3 PUFA reduces the amount of 4-HNE formed during ischemia and reperfusion, abolishing age-associated differences in 4HNE formation. This may impact pathogenesis and the consequences of cardiac ischemia.

  30. What Governs Mitochondrial Survival? Mitochondrial Membrane Permeability Transition and the MPT pore Ca-dependent opening of a high-conductance channel in the inner mitochondrial membrane -regulates membrane permeability may cause loss of membrane potential & ATP

  31. Mitochondrial Membrane Permeability Transition and the MPT pore  Both regulated byHigh CaM; Pi, long chain acyl CoA, spermine, ADP, ROS, protein sulfhydryl and thiol group modification (after peroxidation) AND CARDIOLIPIN!  Collapse of the membrane potential leads to mitochondrial swelling, rapid MPT and pore opening, Loss of ATP production results in cell run down and death.  MPT pore opening releases mitochondrial contents -incl cytochrome c and can trigger caspase activation and the apoptotic cascade.

  32. Mitochondrial Membrane Permeability Transition Confocal measurement of in situ mitochondrial membrane potential and ROS using TMRE and DCF in real time

  33. TMRM fluorescence (mitochondrial membrane potential) Isolated Mitochondria

  34. Modulators of Mean Time to Mito Membrane Permeability Transition SCAVENGING ROS INHIBITS THE MPT

  35. MITOCHONDRIA OF SENESCENT CARDIOCYTES ARE MORE SUSCEPTIBLE TO ROS; RESCUE BY CoQ10

  36. Total Coenzyme Q10 Concentration in Cardiac Myocytes from 6 and 24 mo S-D rats

  37. Reversal of membrane aging requires Omega-3 : Omega-6 PUFA + Intrinsic Antioxidant Systems for improved mitochondrial response to stress that matches the response of young hearts

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