Cardiotoxicity of Hyperamylinemia
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1 Cardiotoxicity of Hyperamylinemia β-cell Dysfunction & Apoptosis Pancreatic β-cell Amylin Oligomers BLOO OD AMYLIN OLIGOMERIZATION HYPERGLYCEMIA Calcium dsreglation dysregulation HYPERAMYLINEMIA HYPERINSULINEMIA Hypertrophy, Remodeling Florin Despa Heart Failure Department of Pharmacology University of California, Davis
2 Patients with Obesity and Type-2 Diabetes Present Cardiac Amylin Accumulation A source of cardiomyocyte Ca 2+ dysregulation Collaborators Kenneth B. Margulies (UPenn) Heinrich Taegtmeyer (UTHS) Donald Steiner (U of Chicago) Sanda Despa (UC Davis) Donald M. Bers (UC Davis) Anne Knowlton (UC Davis) Peter Havel (UC Davis) Lab Members Kaleena Jackson Katie Guglielmino Andy Nguen Tracy Tang Terry Pang Funds: AHA, NSF, Vision Grant - UC Davis
3 3 2 HYPOTHESIS Risk for Cardiac Disease Insulin Resistance Insulin Type-2 Diabetes Insulin 1 Hyperinsulinemia Hyperamylinemia Toxic Amylin Oligomers Hyperglycemia Dyslipidemia HF BLOOD pancreatic β-cell
4 RATIONALE: selection of human heart samples Lean Non-Failing Hearts Lean, Non-diabetes Failing Hearts Obese/Overweight Non-Failing Hearts Obese/Overweight Failing Hearts Type-2 Diabetes Failing Hearts Amylin Oligomers Amylin Oligomers distinct amylin oligomer size distributions
5 5 Amylin Oligomers Accumulate in Heart Failing vs. Non-failing Anti-Amylin Antibody L-NF OW/OB-HF octamer 15 tetramer e trimer 1 kda rimers (% Control) Amylin T 4 Amylin TTrimers L-NF L-HF OW/OB B-NF OW/OB B-HF DM-HF 16-MER OCTAMER TETRAMER TRIMER DIMER FAILING NON-FAILING Amylin Level (% Control) Larger Amylin Oligomers L-NF L-HF OW/OB -NF OW/O OB-HF DM-H F
6 PANCREAS Cardiac Amylin Deposition in Type-2 Diabetic Humans HEART HEART HEART Control 2 µm 2 µm 2 µm 2 µm HEART HEART Anti-Am mylin Ant tibody 2 µm o Red Sta aining Cong 2 µm
7 Amylin Oligomers Circulate Through the Blood Obese, Diabetes and Kidney Failure Obesity and Type-2 Diabetes With Kidney Failure obese T2DM T2DM 16 T2DM T2DM T2DM IAPPP level (a.u.) 12 8 OW/OB DM High MW IAPP (%) 12 Healty BMI < L L IAPP High Le MW evel IAPP (% Con (%) trol) E15 E13 E11 E19 E18 E17 E16 E12 C
8 Acute Effect of Amylin on Isolated Cardiac Myocytes Human: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY Rat: KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY [C Ca] i (nm) 15 Control h-amylin 1 Systolic )r-amylin 5 Diastolic Frequency (Hz) Ca Transi ient Dec cay (s) h-amylin r-amylin
9 Amylin Oligomers Alter the Structure of Sarcolemma in Isolated Cardiac Myocytes Thaps+Ca/Na 2 +carboxyeosin + ]i (nm) [Ca 2 Amylin 5 1 min Ca 2+ l eak (nm/ /s) Passive Ca 2+ Leak Amylin 2.5 µm 2.5 µm control
10 Animal Models Human Amylin Rat Amylin pancreas HIP rat pancreas UCD-T2DM rat 2 Non-fasting Blood Glucose Level cose l) Blood Glu (mg/dl UC CD-T2DM HI IP
11 Amylin Accumulates in the Heart of HIP Rats HIP rat UCD D-T2DM rat 2 µm 2 µm 25 kda Pancreas Heart Pancreas Heart 64 Lysates PD DM 15 kda 32 1 kda HIP UCD-T2TM 16 kda HIP rat
12 Myocardial Insulin Signaling in HIP vs. UCD-T2DM rats 2. p-a Akt/Akt t (a.u.) HIP UCD 1 HIP UCD Insulin: pakt Akt
13 Cardiac Amylin Oligomer Accumulation Alters Ca 2+ Cycling in HIP Rats [Ca a] i (nm) HIP rat HIP UCD 1 5 Systolic Diastolic Frequency (Hz) [Ca a] i (nm) diastolic dysfunction 1 5 UCD rat Systolic Diastolic Frequency (Hz) (s).8 Deca ay time HIP (s).8 Deca ay time UCD
14 End Systolic P (mmhg) Contractile Dysfunction in Pre-diabetic HIP Rats RI IP HI IP Left-Ventricular End Systolic Pressure -dp/dt min (mmhg/ /s) RIP HIP Maximum Rate of Pressure Fall Maximum Rate of Pressure Rise collab. with A. Knowlton (UC Davis) P/dt max (mm mhg/s) d End Diast tolic P (mm mhg) RI IP HI IP Left-Ventricular End Diastolic Pressure RIP HIP
15 Cardiac Amylin Oligomer Accumulation Triggers Remodeling of SERCA HIP rat PD PD DM DM SERCA PD DM PLB PD DM NCX UCD rat SER RCA (% vs. C ) PD DM % vs. PD DM
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