About OMICS Group Conferences

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1 About OMICS Group OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology Open Access, OMICS Group publishes 400 online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also organizes 300 International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions.

2 About OMICS Group Conferences OMICS Group International is a pioneer and leading science event organizer, which publishes around 400 open access journals and conducts over 300 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. OMICS Group has organized 500 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.

The Homeostatic Intracellular Repair Response

Shiley BioScience Center San Diego State

3 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

4 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

5 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, (2004)

6 Central Hypothesis Autophagy is impaired in the setting of MetS and results in the loss of endogenous protection conferred by ischemic preconditioning (IPC)

7 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)

8 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

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

9 Body Weight Gain (g) Fewer Cardiac Autophagosomes MHC mcherry-lc3 Mice Control Diet HFD Days on Diet in DIO Mice Normal Chow 40x High Fat Diet 40x Puncta/ Field Number of Puncta n=7 * n=7 Puncta / Nuclei Puncta/ Nuclei n=7 * n=7 Puncta Size (px 2 ) mcherry LC3 Puncta Size 60x 0 Chow HFD 0 Chow HFD 0 M14 M15 M16 M6 M7 Chow Diet M8 High Fat Diet

GAPDH 4 3 2 1 0 Chow HFD 0 Chow HFD Atg12 2.5 p62 2.

10 Autophagy is Decreased in DIO Mice p62 LC3 Chow HFD 14 LC3-II 5 Beclin-1 LC3II (Density) Beclin-1/ GAPDH Chow HFD 0 Chow HFD Atg p Atg12/ Tubulin p62/ Actin Chow HFD 0.0 Chow HFD

11 MetS in Zucker Obese Rats Body Weight (g) Body Weight p < 0.01 Lean Obese Cholesterol (mg/dl) Serum Cholesterol p < 0.01 Lean Obese Triglyceride (mg/dl) Serum Triglycerides p < 0.01 Lean Obese HOMA Index HOMA p < 0.01 Lean Obese Blood Glucose (mg/dl) Fasting Glucose p < 0.01 Lean Obese Insulin (ng/ml) Serum Insulin p < 0.01 Lean Obese

12 Impaired Autophagy in Adult Myocytes from ZO Rats with MetS 350 LC3-II: Starvation LC3-II (% of Control) Lean Control Starved ZO LC3 Rho Lean Ctrl Lean Starve ZO Ctrl ZO Starve p-s6k (% of Control) p-s6k: Rapamycin Lean Control Rapamycin ZO LC3-II (% of Control) LC3-II: Rapamycin Lean Control Rapamycin ZO p62 (% of Control) p62: Rapamycin Control Rapamycin Lean ZO 12

13 Autophagy is Reduced in in ZO Rats with MetS 0.12 Cardiac LC3-II 0.35 Cardiac Atg Density Density LC3 Lean Obese

14 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) * N.S. 0 Cont. IPC Cont. IPC Lean Obese

15 Obesity and Hypercholesterolemia in High Fat/ Fructose Fed Yucatan Pigs Body Weight (kg) Yucatan Mini Pigs Body Weight HFFD Diet Chow Diet Time on Diet (Weeks) Cholesterol (mg/dl) Fasting Cholesterol HFFD Diet Chow Diet Time on Diet (Weeks) 100 Abdominal Girth 25 Calculated Body Fat (cm) (%) Chow HFFD 0 Chow HFFD

16 Depressed Autophagy in Obese Yucatan Pigs Atg5 Rho p62 Rho Chow HFD Chow HFD 1.2 Cardiac Atg5 2.5 Cardiac p Atg5/ Rho p62/ Rho Chow HFFD 0.0 Chow HFFD

17 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) n=6 No IPC n=2 IPC Lean Farm Pigs n=2 Lean IPC n=2 HFFD IPC Yucatan Mini-pigs

18 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?

19 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

20 Methods (1) 19 patients (38 samples) undergoing cardiac surgery Right atrial tissue ( mg) obtained before cross-clamping the aorta and after its removal Western blotting used to measure autophagy proteins (Beclin-1, Atg5-12, SQSTM1/p62)

21 Methods (2) The perioperative autophagic response was correlated with the morbidity and mortality risk calculated from STS Adult Cardiac Surgery Database

22 Actin Levels Are Unaffected By 0.8 Cardiac Stress 0.6 Actin 0.4 N.S Before After Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b Actin

23 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

24 Cardiac Stress Is Associated with Decreased Levels of Atg Atg p = Before After Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b Atg5-12

25 Cardiac Stress Is Associated with 0.5 Decreased Levels of p p p = Before After Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b P62/SQSTM1

26 Cardiac Stress Depletes Key Autophagy Proteins Signal Density n =19 Patients Beclin-1 Atg 5-12 p62 p = * p =0.002 * p = * 0.0 Before After Before After Before After

27 Operative Risk Correlates with Changes in Autophagy Morbidity/ Mortality Risk (%) r 2 = 0.30 p = Change in p62 (Density Units)

28 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

29 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

30 Preparing for OMICS 2013

31 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

33 Mechanism is Adaptive Autophagy Mitochondrion Atg5-Atg12 p62 Beclin-1 LC3-GFP Modified from T. Shintani et al., Science 306, (2004)

34 Conclusion The findings suggest that the future of better cardioprotection lies with our ability to enhance this important adaptive response to ischemic stress

35 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

36 Increased Autophagic Flux is Associated with Reduced M/M Risk Autophagy Proteins Calculated M/M Risk vs. p62 Signal Density n =19 Patients Beclin-1 Atg 5-12 p62 p = * p =0.002 Before After Before After Before After * p = * Morbidity/ Mortality Risk (%) r 2 = 0.30 p < Change in p62 (Density Units)

37 Summary Autophagy flux is inversely correlated with operative risk Autophagy in humans is an endogenous self protective response

38 Thanks' for your kind attention!!!!!! 38

39 Let Us Meet Again We welcome you all to our future conferences of OMICS Group International Please Visit:

About OMICS Group Conferences

About OMICS Group Conferences About OMICS Group OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of