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Stress and the Aging Heart

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  1. Department of Molecular and Cellular Sport Medicine (Head: Prof. Dr. W. Bloch) Institute of Cardiology and Sport Medicine German Sport University Cologne Stress and the Aging Heart PD Dr. Klara Brixius

  2. Stress and the Aging Heart ‚Aging‘ Getting older Getting old Cellular Growth/Regeneration Degeneration/Senescence

  3. Oxidative Stress Stress and the Aging Heart Cardiac Stress

  4. Stress and the Aging Heart ‚Oxidative Stress‘ and Antioxidant Defense Mechanisms Gender Differences in the Aging Heart, Prevention and Therapeutic Consequences

  5. O O O O O2 O O Superoxide Anion Oxidative Stress : Definition Oxygen Molecule O 2

  6. Oxidative Enzymes : Cytochrome C Oxidase Oxidative Phosphorylation Inner Side Matrix Outer Side Intermembraneous Space

  7. Oxidative Enzymes : NAD(P)H-Oxidases

  8. ATP ADP Adenosine Hypoxanthine Physical Exercise Ischemia O2 + Urate Xanthine oxidase Xanthine oxidase Xanthine + O2 Oxidative Enzymes : Xanthine-Oxidases Modified from Tossios and Mehlhorn 2004, Blickpunkt der Mann 2: 36-39

  9. Cellular Dysfunction Lipid peroxidation (cellular membranes) Protein oxidation (Cytosol) DNA oxidation (Nucleus) Webside Prof. S. Harding Imperial College London Hyperglycemia Cardivascular Risk Factors Angiotension, etc. oxLDL ROS and the Aging Heart ROS and the Aging Heart Cellular Dysfunction

  10. Hyperglycemia Cardivascular Risk Factors Angiotension, etc. oxLDL ROS and the Aging Heart Tissue Degeneration modified from Brandes et al. Cardiovasc Res (2005) 66: 286-294

  11. Oxidative Stress : Definition Antioxidative Defense ROS

  12. O2 OH ROS and Antioxidative Defense Mechanisms Cytochrome C Oxidase NAD(P)H Oxidase Xanthin Oxiase O2 Gluthatione Peroxidase (Se, GSH) Katalase SOD (Mn, Cu) H2O H2O2 • Radical Buffer Systems: • Vitamines • Thioredoxins/Peroxiredoxins • Proteins (Albumin, Thiols) 1O2

  13. No increase in the vessel/myocyte ratio in MnSOD-knockout mice after endurance training Wild type MnSOD-KNO 8-Isoprostan * 5 * Wild type MnSOD-KNO 4 3 Vessel/myocyte 2 1 Strassburger et al. Free Radical Biology & Medicine (2005) 38: 1458-1470 0 n=6 n=6 n=9 n=9 Con Train Con Train *: p<0.05 Brixius, Bloch et al. 2006, in preparation

  14. Adaptation of Antioxidative Defense Mechanisms Maladaptation Antioxidants Adaptation Oxidative Stress modified from Gutteridge 1992, Free Rad Res Comm 19: 598-620

  15. p=0.06 p=0.06 p=0.07 Differential Down-Regulation of Peroxiredoxin Isoforms in Human Failing Myocardium Peroxiredoxin 6 Peroxiredoxin 4 Peroxiredoxin 5 Peroxiredoxin 1 Peroxiredoxin 2 Peroxiredoxin 3 NF DCM NF DCM NF DCM NF DCM NF DCM NF DCM DU/µg prot. p=0.08 DU/µg prot. DU/µg prot. DU/µg prot. DU/µg prot. DU/µg prot. 20 35 50 120 80 240 30 70 210 100 16 40 25 60 180 80 12 30 50 150 20 60 40 120 15 8 20 30 90 40 10 20 60 4 10 20 5 10 30 0 0 0 0 0 0 NF DCM NF DCM NF DCM NF DCM NF n=6 DCM NF DCM Number of experiments,NF and DCM: n=6 each Brixius, Bloch, 2006, in preparation

  16. Stress and the Aging Heart ‚Oxidative Stress‘ and Antioxidant Defense Mechanisms Gender Differences in the Aging Heart Therapeutic Consequences ?

  17. Stress and the Aging Heart: Gender Vina et al. 2005, FEBS Letters 579: 2541-2545

  18. Antioxidative Mechanisms of Estrogenes Estrogen ER Non genomic Rapid Antioxidative Enzymes Oxidative Defense  Estrogen ER Genomic Slow ERE

  19. Body height, m 1.75 ± 0.08 1.62 ± 0.07 § Blood pressure, mm Hg 121/75 ± 9/7 114/70 ± 12/8 + Heart rate, bpm 66 ± 11 69 ± 11 LV mass, g 155 ± 33 111 ± 25 § Gender-Specific Differences in Cardiac Function Men Women (n = 229) (n = 164) Age, y 46 ± 12 44 ± 13 Body weight, kg 74 ± 8 61 ± 9§ Stroke volume, ml/beat 78 ± 16 64 ± 12§ Stroke work, g - m/beat 136.15 ± 30.38 105.21 ± 25.06§ De Simone et al., Hypertension 31: 1077-1082, 1998 *P<05; +P<005; §P<0001 for gender difference within age stratum.

  20. Ratio of Stroke Work to LV Mass in Normotensive, Normal-Weight Individuals Stroke Work/LV Mass, Stroke Work Index/LV 2 g-m/beat per gram Mass, g-m/beat/m per gram Men (n = 229) 0.89 ± 0.17 0.47 ± 0.1 LV indicates left ventricular * * P < 0001 vs men. * Women (n = 164) 0.97 ± 0.23 0.59 ± 0.15 Gender-Specific Differences in Cardiac Function De Simone et al., Hypertension 31: 1077-1082, 1998

  21. Gender Differences in Mitochondrial Function Male 6000 * 4000 pmol O2 * s-1 * g tissue-1 Female 2000 0 Female Male Justo et al., Am J Physiol 289: C372-378, 2005

  22. Gender Differences in Oxidative Defense Mechanisms Vina et al. 2005, FEBS Letters 579: 2541-2545

  23. Gender Differences in ROS Generation at Physical Exercise 30 s cycle sprint 20 min rest Esbjörnsson-Liljedahl et al. J Appl Physiol 93: 1075-1083, 2002

  24. + Gender Differences in Telomere Lengthening Estrogen Akt, NO Cherif et al. (2003) Nucleic Acids Research 31: 1576-1583 modified from Brandes et al. Cardiovasc Res (2005) 66: 286-294

  25. Gender Differences in Oxidative Stress and Cardiac Aging - Prevention and Therapeutical Consequences: Conclusions and Perspectives Hormonal Replacement Therapy Nutritional Supplementation (e.g. phytoestrogenes?, gender-specific nutrion recommendations...)

  26. Oxidative Stress and Physical Exercise ‚Cologne Marathon‘ Reactive Oxygen Metabolites 700 before after 600 500 400 Arbitrary Units 300 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 + Antioxidants Laatsch, Türk, Predel Brixius, Bloch et al. 2006 unpublished results

  27. Gender Differences in Oxidative Stress and Cardiac Aging - Prevention and Therapeutical Consequences: Conclusions and Perspectives Hormonal Replacement Therapy Nutritional Supplementation (e.g. phytoestrogenes?, gender-specific nutrion recommendations...) Physical exercise in young and old persons

  28. The Cologne Cardiac Anti-Aging Program

  29. Kölle Alaaf ! Kölle Alaaf ! Kölle Alaaf !