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2017 Cardiovascular Research Day Abstract Book

7 Diabetic Hfpef in a

7 Diabetic Hfpef in a Rat Model of Systemic Amylin Dyshomeostasis Miao Liu, PhD 1 • Nirmal Verma, PhD 1 • Analia Loria, PhD 1 • Sanda Despa, PhD 1 • Florin Despa, PhD 1 1Pharmacology and Nutritional Sciences, University of Kentucky Postdoc Diabetic heart failure with preserved ejection fraction (HFpEF) is a complex disease characterized by diastolic dysfunction, altered insulin sensitivity and multiple organ impairments. Amylin, a β-cell hormone co-secreted with insulin, participates in normal glucose regulation, but is also known to induce insulin resistance and to form pancreatic amyloid when oversecreted (hyperamylinemia). Accumulating data from several laboratories have confirmed that, in addition to pancreatic islets, the hearts, kidneys and brains of patients with type-2 diabetes contain also abnormally increased levels of aggregated amylin. Our overall hypothesis is that the interplay between insulin resistance and hyperamylinemia results in toxic accumulation of aggregated amylin in the microvasculature that adversely affects function of multiple organs, including, but not limited to, the heart. Here, we used rats overexpressing human amylin in the pancreas (HIP rats) to test whether a “human” hyperamylinemia predisposes to HFpEF. Wild-type (WT) littermates expressing non-amyloidogenic rat amylin served as control. Hearts and kidneys of HIP rats showed amylin deposition in capillaries, intravascular macrophage accumulation, microhemorrhages and loss of vascular endothelial cell coverage and tight junctions. These changes were associated with diastolic dysfunction, cardiac hypertrophy and mid-range cardiac ejection fraction (~50%). HIP rats also had increased blood pressure and renal dysfunction, including diuresis, natriuresis, creatinine clearance and microalbuminuria. Abundant amylin deposition was detected in HIP rat red blood cells (RBCs). Amylin-loaded RBCs have altered deformability and increased adherence to cultured endothelial cells. Intravenous infusion of RBCs from HIP rats in WT rats resulted in release of amylin in plasma and capillaries, attachment of RBCs to the vascular endothelium, intravascular macrophage accumulation and microhemorrhages. In conclusion, hyperamylinemia provokes systemic amylin dyshomeostasis which negatively affects cardiac and renal function via amylin-mediated microvascular injury. Circulating level of amylin may serve as a biomarker of diabetic HFpEF and therapeutic target to reduce the development/progression of HFpEF. 23

8 Azithromycin Therapy Reduces Cardiac Inflammation and Mitigates Adverse Cardiac Remodeling after Myocardial Infarction: Potential Therapeutic Targets Ahmed Al-Darraji, PharmD 1 • Dalia Haydar 2 • Lakshman Chelvarajan, PhD 3 • Himi Tripathi, PhD 3 • Bryana Levitan 4 • Shaojing Ye, PhD 3 • Vincent Venditto, PhD 5 • John Gensel, PhD 4 • David Feola, PhD 5 • Ahmed Abdel-Latif, MD, PhD 6 1Pharmacology and Nutritional Sciences, University of Kentucky • 2 Pharmacy College, University of Kentucky • 3 SAHA cardiovascular center, University of Kentucky • 4 Physiology, University of Kentucky • 5 College of Pharmacy, University of Kentucky • 6 Cardiology, University of Kentucky Graduate Student Abstract Introduction and Hypothesis: Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-AMI inflammation. Pro-inflammatory macrophages (M1-like) can lead to adverse cardiac remodeling and heart failure while regulatory/reparative macrophages (M2-like) enhance tissue healing. Shifting the balance between M1 and M2 macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards an M2-like phenotype in animal and human studies. We hypothesized that using AZM can decrease adverse cardiac remodeling and improve heart function following MI. Methods and results: Male mice (C57BL/6, 6–8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle control starting 3 days prior to MI and continued to day 7 post-MI. We observed significant reduction in mortality with AZM therapy. AZM-treated mice showed reduction in M1-like (CD45+/Ly6G-/F4-80+/CD86+) and increase in M2-like (CD45+/Ly6G-/F4-80+/CD206+) macrophages leading to significant reduction in the M1/M2 ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with significant reduction in pro-inflammatory and increase in anti-inflammatory cytokine production as assessed by real-time PCR. AZM treatment was associated with increased neutrophil apoptosis, a known signal for shifting macrophages towards an M2-like phenotype. Finally, AZM treatment was associated with enhanced cardiac recovery, smaller scar size and enhanced angiogenesis. Conclusion: Azithromycin plays a cardioprotective role post-MI through attenuating inflammation and enhancing cardiac recovery. Long term and human translational studies are planned to examine the therapeutic applications of AZM. 24

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