Adipose Tissue Dysfunction and Diabetic Cardiovascular Disease Xin-Liang Ma, MD, PhD Thomas Jefferson University Philadelphia, PA USA
CVD As The #1 Causes of Death In USA Male Female Heart Disease and Stroke Statistics--2010 Update: A Report From the American Heart Association, Circulation, 121, e46-215, 2010
Obesity/Diabetes = Common Soil for Cardiovascular Disease CHD Hypertension Stroke Heart failure Arrhythmia Disorder of Glucose Metabolism Disorder of Lipid Metabolism OBESITY
What Matters More? Quantity Vs. Quality
OBESE LEAN Adipose tissue Dysregulation ANTI-INFLAMMATORY PROFILE: IL-4,IL-10,IL-13 Normal metabolic function Normal vascularization Immune cells: M2 macrophages, eosinophils and Tregs PRO-INFLAMMATORY PROFILE: IFNᵧ, TNF-α,MCP-1,IL-6,IL-1β, Metabolic dysfunction, Severe hypoxia, Adipocyte necrosis Immune cells: M1 macrophages (crown-like structures), CD4 + T Iymphocytes, CD4 + T Iymphocytes, B Iymphocytes and mast cells Adipocyte M2 Macrophage Eosinophil Treg Capillaries M1 Macrophage B Lymphocyte Neutrophil Mast cells T Lymphocyte
Adipose Tissue Dysfunction Adipogenesis intact (minimal hypertrophy) Sufficient storage capacity Regulated lipolysis No inflammation Insulin sensitive Positive Energy balance Subcutaneous Adipose tissue expansion Decreased adipogenesis (adipocyte hypertrophy) Storage capacity compromised Increased lipolysis Low-grade inflammation Insulin resistance Pro-inflammatory adipokine profile Increased visceral adipose tissue Free fatty acids Adverse Impact Upon Liver, Skeletal Muscle, Endothelial Cells, and Cardiomyocytes
Adipokines, Adipocytokines Free Fatty Acids Lysophospholipid Lactate Glutamine Cytokines (TNF, Interleukins,PAI-1) Growth Factors (TGFb,IGF-1, IGFBP FGF, EGF, IGF-1 IGFBP, FGF, EGF) Hormones (Angiotensin, Estrogen, Prostaglandins) Leptin 1994 Adiponectin 1995
Largest Endocrine Organ Leptin Adiponectin Adipose Derived Hormones
Is Adipocyte Endocrine Function Altered in Obesity/Diabetes?
Association of Serum Leptin Concentration with BMS and Waist Circumference in Non-Diabetic and Diabetic Men and Women BMJ 1996;313:965-969
Correlations between Serum Leptin and BMS and WBGU European Journal of Endocrinology (1998) 139 598 604
Paradoxical Decrease of Adiponectin in Obesity r=-0.66 p<0.0001 r=-0.48 p<0.0001 Non-obese subjects: men; 7.7 ± 3.1 µg/ml, women; 10.6 ± 7.3, p < 0.0001 Obese subjects: men; 2.8 ± 2.1 µg/ml, women; 4.8 ± 4.0, p < 0.0001 Arita, et al., BBRC 257;79,1999
Reduced Plasma Concentrations of Adiponectin in Type 2 Diabetic Patients Arterioscler Thromb Vasc Biol 2000;20;1595-1599
Healthy Adiponectin Leptin
Adiponectin Obesity/Diabetes Leptin
Does Adipocyte Endocrine Unbalance Play Important Roles in Diabetic Heart Injury?
Leptin From a Fat Fighter to a Risk Factor Ob/ob Db/db Reduces Appetite
Reduced Adiponectin Level is Associated with Severity of Coronary Artery Disease Int Heart J 2007; 48: 149-153
Am J Cardiol 2007;100:569 574
Serum Adiponectin is A Predictor of Coronary Heart Disease: A Population-Based 10-Year Follow-up Study in Elderly Men The Journal of Clinical Endocrinology & Metabolism 92(2):571 576
Future Adverse Cardiac Events Can Be Predicted by Persistently Low Plasma Adiponectin Concentrations in Men and Marked Reductions of Adiponectin in Women after Acute Myocardial Infarction Atherosclerosis 194 (2007) 204 213
Usefulness of Adiponectin to Predict Myocardial Salvage Following Successful Reperfusion in Patients with Acute Myocardial Infarction Am J Cardiol 2008;101:1712 1715
Three Questions for A Top-Down Translational Research Causative? Mechanisms? Target?
Obesity/Diabetes Adiponectin Vascular Injury Cardiomyocyte Injury Morbidity of IHD Mortality of IHD Tao et al, Circulation, 115:1408-1416, 2007
Adiponectin Biological Functions AMPK Agonists Anti-Oxidative/Anti-Nitrative Anti-Oxidative/Anti-Nitrative Stress AMPK AMPK Anti-Inflammatory Metabolic/Insulin Sensitization Wang et al, Circulation, 119:835-844,2009
APPL1 ncdase AMPK Anti-Inflammatory Anti-Oxidative/Nitrative Insulin Sensitization Metabolic Regulation Wang et al, Circ Res, 114:792-805,2014
Normal Heart Diabetic Heart PKA AMPK Akt X PKA AMPK Akt Cardioprotection Loss of Cardioprotection Wang et al, ATVB, 32:934-942, 2012
Obesity/Diabetes: Adipose Endocrine Dysfunction Adiponectin Leptin
APN in HF Is Controversy
High Adiponectin Levels Are Associated with Increased Mortality and Heart Failure NORMAL LEVEL
GRK2-Mediated AdipoR1 Phosphorylation Contributes to the Development of Ischemic Herat Failure APN X AdipoR1 P GRK2 Anti-Inflammatory Anti-Oxidative/Anti-Nitrative Stress Cardiometabolic Stimulation BNP Wang et al, Circulation. 2015;131:1392-1404
Systemic Adiponectin Dysfunction Novel Player in Post-MI Cardiac Remodeling
Post-Ischemic Remodeling Remodeling
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D o t s / F i e l d F o l d O v e r S h a m M I / R D o t s / F i e l d F o l d O v e r S h a m M I / R Merged RFP GFP p 6 2 / S A F o l d O v e r S h a m M I / R L A M P 2 / S A % o f S h a m M I / R L C 3 I I / S A F o l d O v e r S h a m M I / R B e c l i n - 1 / S A F o l d O v e r S h a m M I / R A WT APNKO 1. 5 2. 0 1. 0 2. 0 LC3I LC3II Beclin-1 Sham MI/R MI/R Sham MI/R MI/R 14kD 16kD 60kD 1. 0 0. 5 * 1. 5 1. 0 0. 5 0. 8 0. 6 0. 4 0. 2 * 1. 5 1. 0 0. 5 * αsa 43kD 0. 0 W T A P N K O W T A P N K O 0. 0 W T A P N K O 0. 0 W T A P N K O W T A P N K O 0. 0 W T A P N K O Sham MI/R MI/R Sham MI/R MI/R B P62 LAMP2 WT APNKO Sham MI/R MI/R Sham MI/R MI/R 62kD 110kD 1. 0 0. 8 0. 6 0. 4 0. 2 * ** 3 2 1 * 0. 8 0. 6 0. 4 0. 2 ** 8 0 6 0 4 0 2 0 ** αsa 43kD 0. 0 W T A P N K O W T A P N K O Sham MI/R MI/R 0 W T A P N K O 0. 0 W T A P N K O W T A P N K O Sham MI/R MI/R 0 W T A P N K O C WT APNKO Sham MI/R MI/R Sham MI/R MI/R 1 5 0 ** 4 3 0 0 6 1 0 0 3 2 2 0 0 ** 4 ** 5 0 1 0 0 2 1 0 W T A P N K O W T A P N K O 0 W T A P K N O 0 W T A P N K O W T A P N K O 0 W T A P N K O Sham MI/R MI/R Autophagosome Sham MI/R MI/R Autolysosome
AKNOWLEDGEMENTS Current Members Yajing Wang, MD, PhD Wayne Bond Lau, MD Yaping Guo, MD Yue Chen, MD Han Wang, MD Wenjun Yan, MD,PhD Lu Gan, PhD Bernard Lopez, MD, MS Theodore A. Christopher, MD Ma s Laboratory Past Key Members Feng Gao, MD,PhD Huirong Liu, MD,PhD Ling Tao, MD,PhD Jun Pu, MD, PhD Wei Yi, MD, PhD Yang Sun, MD, PhD Key Collaborators Erhe Gao, MD, PhD Walter Koch, PhD