ΑΡΙΣΟΣΕΛΕΙΟ ΠΑΝΕΠΙΣΗΜΙΟ ΘΕΑΛΟΝΙΚΗ ΣΜΗΜΑ ΒΙΟΛΟΓΙΑ ΤΠΟΚΤΣΣΑΡΙΚΟΙ ΜΗΧΑΝΙΜΟΙ ΠΡΟΑΡΜΟΓΗ ΣΟ ΔΙΑΒΗΣΙΚΟ ΜΤΟΚΑΡΔΙΟ: ΜΙΑ ΕΝΑΛΛΑΚΣΙΚΗ ΜΟΡΦΗ ΕΝΔΟΓΕΝΟΤ ΚΑΡΔΙΟΠΡΟΣΑΙΑ Αντιγόνη Λάζου Καιηγθτρια Φυσιολογίας Σεμινάρια Ομάδων Εργασίας Ελληνικής Καρδιολογικής Εταιρείας Θεσσαλονίκη, 16 Φεβρουαρίου, 212
Total number Arrhythmia score IS/AR (%) % of preischemic values Preconditioning-like effect of acute diabetes in experimental studies Lower sensitivity of diabetic rat heart to ischemia-reperfusion injury 4 3 Size of infarction 75 5 Recovery of LVDP C I-PC D 2 25 1 6 PVC 5 Arrhythmias severity 4 4 2 3 2 1 p<.5 vs C Ravingerova, Adameova...Lazou (21). Exp Clin Cardiol 15:68
Potential mechanisms of preconditioning-like protection in the diabetic myocardium Alterations in the metabolism of glucose, high glucose acting as a PC mimetic in the non-diabetic myocytes Abnormal calcium handling calcium PC Increased production of ROS coupled with higher levels of antioxidants Activation of PKCe Increased MAPK activity enhanced ERK1/2 activation Increased PI3K/Akt and enos activity Increased HIF1-a, VEGF and decreased inflammation and fibrosis
nmol/g ww nmol/g ww nmol/g ww Pro-oxidative and anti-oxidative effects in the myocardium of diabetic and ischemia-preconditioned rats 27 22 17 12 7 Antioxidants C D I-PC 42 32 22 12 6 4 2 TBARS BL I 2 CoQ9 CoQ1 -toc 2 C I-PC D p<.5 vs C p<.5 vs nondiabetic Ravingerova, Adameova...Lazou (21). Exp Clin Cardiol 15:68
IS/LV (%) IS/AR (%) Effects of PI3K inhibition on the size of myocardial infarction in diabetic and high glucose-preconditioned rat heart 5 Size of infarction 4 Size of infarction 4 3 2 3 2 1 1 C C+W GPC GPC+W C C+W D D+W C control W wortmannin GPC preconditioned with high glucose D diabetic p<.5 vs C p<.5 vs GPC or D Ravingerova, Adameova...Lazou (21). Exp Clin Cardiol 15:68
% of preischemic values IS/AR (%) Loss of protection against I/R injury in a double-disease model (acute diabetes + hypercholesterolemia) Myocardial infarction 4 3 2 1 C D D+HCH p<.5 vs control Recovery of LVDP 6 4 C control D diabetes HCH hypercholesterolemia 2 C D D+HCH Ravingerova...Lazou (21). Exp Clin Cardiol 15:68 Adameova et al (27). Mol Cell Biochem 295:129
Energy metabolism in the heart is altered by developmental, dietary and pathophysiological stimuli
PPARs: Peroxisome proliferator-activated receptors Ligand-activated transcription factors, members of the nuclear receptor superfamily Three isoforms identified: α, β/δ and γ Major transcriptional regulators of energy and lipid homeostasis Physiological functions PPARα: fatty acid oxidation PPARγ: fat storage, insulin resistance PPARβ/δ: fatty acid oxidation but mostly unclear Newly emerged functions anti-inflammatory, anti-proliferative, antiischemic
PPAR/GAPDH PPAR / GAPDH PPAR/GAPDH PPAR/GAPDH PPAR / GAPDH PPAR expression in the diabetic rat heart: effect of I/R.3 BL PPAR- I/R.2.25.2 PPAR-g.1.15.1..5.12.9 PPAR-b/d. C D D+HCH.6.3..2 PPAR-g.15.1.5 BL I/R PPAR-g.1. Non-D D - p<.5 vs Non-D, - p<.5 vs BL. C DH DH+S Ravingerova...Lazou (27). JMCC 42:S22 Ravingerova Lazou (211). Gen Physiol Biophys 3:329
LVDP(%) Infarct size (%LV) Infarct size (% LV) PPARα and β/δ agonists protect the heart against I/R induced damage 4 2 5 4 NORMAL DIABETIC 6 C Wy-1643 3 2 1 4 2 C GW742 GW/GSK p<.5 vs C p<.5 vs GW742 C p<.5 vs C Wy-1643
Conclusions Experimentally induced diabetes mellitus may trigger adaptive processes in the myocardium in, at least, the early stage of the disease that are analogous to short-term cardioprotection in the non-diseased preconditioned myocardium Response to I/R in the diabetic heart may be attenuated by concomitant pathology, such as HCH, and it is associated with changes in gene expression of PPARs Enhanced PPAR activity is implicated in the mechanisms of enhanced resistance to ischemia in these animal models. Thus, PPARs might represent an important therapeutic target in the management of ischemic heart disease in patients with or without metabolic disorders.
Γργαστήριο Φσσιολογίας, Τμήμα Βιολογίας, Α.Π.Θ. Γλεσθερία Γαλάτοσ Γλεσθερία Μπαρλάκα Τάρα Κέλλσ Institute for Heart Research, Slovak Academy of Sciences Dr Tanya Ravingerova Faculty of Pharmacy, Comenius University Dr Adriana Adameova