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The Homeostatic Intracellular Repair Response (HIR 2 ) And Heart Surgery 3 rd International Conference on Clinical and Experimental Cardiology Hilton Chicago, Northbrook, USA, 2013 Bruce R. Ito, Roberta A. Gottlieb, Robert M. Mentzer, Jr. Donald P. Shiley BioScience Center San Diego State University San Diego, CA School of Medicine/WSU CVRI Wayne State University Detroit, MI
The Homeostatic Intracellular Repair Response (HIR 2 ) HIR 2 is a lysosomal adaptive response to stress Preclinical evidence indicates it is manifest in multiple organs In the heart it is a protective response to ischemia-reperfusion
Autophagy: A Survival Pathway Mitochondrion Pre-autophagosomal structure Atg5-Atg12 Beclin-1 Phagophore p62 Autophagolysosome LC3 Autophagosome Lysosome Modified from T. Shintani et al., Science 306, 990-995 (2004)
Central Hypothesis Autophagy is impaired in the setting of MetS and results in the loss of endogenous protection conferred by ischemic preconditioning (IPC)
Metabolic Syndrome (MetS) Characterized by obesity, HC, dyslipidemia, and insulin resistance Increased risk of death from myocardial infarction and stroke Prevalence in the USA estimated at >30% of the population; >20% Japan (and rapidly increasing)
Methods Utilized 3 translational models of MetS LC3-mCherry transgenic mice fed a high fat diet (HFD) Genetic Zucker obese (ZO) rats Yucatan pigs fed a high fat/high fructose diet (HF/HF) Assessed autophagy (puncta, Western blot) Measured infarct size (TTC) and response to ischemic preconditioning (IPC)
Body Weight Gain (g) Fewer Cardiac Autophagosomes 14 12 10 8 6 4 2 0 MHC mcherry-lc3 Mice Control Diet HFD 0 20 40 60 80 100 120 Days on Diet in DIO Mice Normal Chow 40x High Fat Diet 40x Puncta/ Field 400 300 200 100 Number of Puncta n=7 * n=7 Puncta / Nuclei 5 4 3 2 1 Puncta/ Nuclei n=7 * n=7 Puncta Size (px 2 ) 250 200 150 100 50 mcherry LC3 Puncta Size 60x 0 Chow HFD 0 Chow HFD 0 M14 M15 M16 M6 M7 Chow Diet M8 High Fat Diet
Autophagy is Decreased in DIO Mice p62 LC3 Chow HFD 14 LC3-II 5 Beclin-1 LC3II (Density) 12 10 8 6 4 2 Beclin-1/ GAPDH 4 3 2 1 0 Chow HFD 0 Chow HFD Atg12 2.5 p62 2.0 Atg12/ Tubulin 2.0 1.5 1.0 p62/ Actin 1.5 1.0 0.5 0.5 Chow HFD 0.0 Chow HFD
MetS in Zucker Obese Rats Body Weight (g) 600 500 400 300 200 Body Weight p < 0.01 Lean Obese Cholesterol (mg/dl) 250 200 150 100 50 0 Serum Cholesterol p < 0.01 Lean Obese Triglyceride (mg/dl) 800 600 400 200 0 Serum Triglycerides p < 0.01 Lean Obese HOMA Index 300 250 200 150 100 50 0 HOMA p < 0.01 Lean Obese Blood Glucose (mg/dl) 140 120 100 80 60 Fasting Glucose p < 0.01 Lean Obese Insulin (ng/ml) 40 30 20 10 0 Serum Insulin p < 0.01 Lean Obese
Impaired Autophagy in Adult Myocytes from ZO Rats with MetS 350 LC3-II: Starvation LC3-II (% of Control) 300 250 200 150 100 50 Lean Control Starved ZO LC3 Rho Lean Ctrl Lean Starve ZO Ctrl ZO Starve p-s6k (% of Control) 140 120 100 80 60 40 20 0 p-s6k: Rapamycin Lean Control Rapamycin ZO LC3-II (% of Control) 160 140 120 100 80 60 LC3-II: Rapamycin Lean Control Rapamycin ZO p62 (% of Control) 140 120 100 80 60 p62: Rapamycin Control Rapamycin Lean ZO 12
Autophagy is Reduced in in ZO Rats with MetS 0.12 Cardiac LC3-II 0.35 Cardiac Atg 5 0.10 0.30 Density 0.08 0.06 Density 0.25 0.20 0.04 0.15 0.02 0.10 LC3 Lean Obese
Impaired Pre-conditioning in Zucker Obese Rats with MetS Lean Cont. Lean IPC Obese Cont. Obese IPC 80 Infarct Size in Zucker Rats Infarct Size (% AAR) 60 40 20 * N.S. 0 Cont. IPC Cont. IPC Lean Obese
Obesity and Hypercholesterolemia in High Fat/ Fructose Fed Yucatan Pigs Body Weight (kg) 40 35 30 25 20 15 10 Yucatan Mini Pigs Body Weight HFFD Diet Chow Diet 0 1 2 3 4 5 6 7 8 9 Time on Diet (Weeks) Cholesterol (mg/dl) 1400 1200 1000 800 600 400 200 0 Fasting Cholesterol HFFD Diet Chow Diet 0 1 2 3 4 5 6 7 Time on Diet (Weeks) 100 Abdominal Girth 25 Calculated Body Fat 90 20 (cm) 80 70 (%) 15 10 60 5 50 Chow HFFD 0 Chow HFFD
Depressed Autophagy in Obese Yucatan Pigs Atg5 Rho p62 Rho Chow HFD Chow HFD 1.2 Cardiac Atg5 2.5 Cardiac p62 1.0 2.0 Atg5/ Rho 0.8 0.6 0.4 p62/ Rho 1.5 1.0 0.2 0.5 0.0 Chow HFFD 0.0 Chow HFFD
Impaired Preconditioning in Obese Swine with MetS Effect of High Fat - High Fructose Diet on Ischemic Preconditioning (IPC 1 x10') in Pigs Infarct Size (% of AAR) 60 50 40 30 20 10 0 n=6 No IPC n=2 IPC Lean Farm Pigs n=2 Lean IPC n=2 HFFD IPC Yucatan Mini-pigs
Summary Animal models of metabolic syndrome show impaired autophagy and loss of cardioprotection But do we know about autophagy and cardioprotection in the human heart?
Autophagy in the Human Heart Upregulated autophagy in failing heart decreased after mechanical unloading Kassiotis et al. Circulation 2009 Impaired autophagy associated with postoperative atrial fibrillation Garcia et al. J Thorac Cardiovasc Surg 2011
Methods (1) 19 patients (38 samples) undergoing cardiac surgery Right atrial tissue (200-400 mg) obtained before cross-clamping the aorta and after its removal Western blotting used to measure autophagy proteins (Beclin-1, Atg5-12, SQSTM1/p62)
Methods (2) The perioperative autophagic response was correlated with the morbidity and mortality risk calculated from STS Adult Cardiac Surgery Database
Actin Levels Are Unaffected By 0.8 Cardiac Stress 0.6 Actin 0.4 N.S. 0.2 0.0 Before After Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b Actin
Cardiac Stress Is Associated with Decreased Levels of Beclin -1 Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b Beclin-1
Cardiac Stress Is Associated with Decreased Levels of Atg5-12 1.0 0.8 Atg5-12 0.6 0.4 p = 0.002 0.2 0.0 Before After Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b Atg5-12
Cardiac Stress Is Associated with 0.5 Decreased Levels of p62 0.4 p62 0.3 0.2 p = 0.001 0.1 0.0 Before After Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b P62/SQSTM1
Cardiac Stress Depletes Key Autophagy Proteins Signal Density 0.6 0.5 0.4 0.3 0.2 0.1 n =19 Patients Beclin-1 Atg 5-12 p62 p = 0.001 * p =0.002 * p = 0.001 * 0.0 Before After Before After Before After
Operative Risk Correlates with Changes in Autophagy Morbidity/ Mortality Risk (%) 30 25 20 15 10 5 0 r 2 = 0.30 p = 0.027-0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Change in p62 (Density Units)
Summary Preclinical studies support concept that autophagy is cardioprotective and is impaired in MetS Cardiac surgery and its attendant ischemia is accompanied by accelerated autophagic flux The magnitude of flux increase is inversely correlated with risk
Conclusion Studies evaluating the role of autophagy in setting of I/R are feasible in humans Enhancement of autophagy represents a new clinical approach to myocardial protection during heart surgery
Preparing for OMICS 2013
Acknowledgements Bruce R. Ito Roberta A. Gottlieb Salik Jahania David Sengstock Peter Vaitkevicius Post-doctoral Fellows Zoltan Giricz Allen Andres Students Nandini Ravindran Carlos Bazan 31
Mechanism is Adaptive Autophagy Mitochondrion Atg5-Atg12 p62 Beclin-1 LC3-GFP Modified from T. Shintani et al., Science 306, 990-995 (2004)
Conclusion The findings suggest that the future of better cardioprotection lies with our ability to enhance this important adaptive response to ischemic stress
The Homeostatic Intracellular Repair Response (HIR 2 ) HIR 2 is a lysosomal adaptive response to stress Represents a new approach to myocardial protection Preclinical evidence indicates it is manifest in multiple organs and is cardioprotective
Increased Autophagic Flux is Associated with Reduced M/M Risk Autophagy Proteins Calculated M/M Risk vs. p62 Signal Density 0.6 0.5 0.4 0.3 0.2 0.1 0.0 n =19 Patients Beclin-1 Atg 5-12 p62 p = 0.001 * p =0.002 Before After Before After Before After * p = 0.001 * Morbidity/ Mortality Risk (%) 30 25 20 15 10 5 r 2 = 0.30 p < 0.03 0-0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Change in p62 (Density Units)
Summary Autophagy flux is inversely correlated with operative risk Autophagy in humans is an endogenous self protective response
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