Abstract 189: Novel Drug Development Controlling Residual Inflammatory Risk in Diabetic Atherosclerotic Disease

Abstract

Sustained inflammation is a crucial pathologic component in atherosclerosis and type 2 diabetes (T2D). A common molecular player driving auto-inflammation in both diseases is the CD40/CD154 inflammatory dyad. By normalizing the aberrant contact dependent interaction of the CD40/CD154 dyad, and resultant auto-inflammation, multiple studies have shown both prevention and therapeutic efficacy in both diseases. We designed a series of peptides derived from the CD154 protein sequence that are capable of binding directly to the CD40 receptor to interrupt the inflammatory signal pathways. Two peptides, KGYY6 and KGYY15, were highly effective, initially demonstrating efficacy in type one diabetes mouse models. KGYY6 was chosen for additional testing in the T2D model with atherosclerosis. ApoE-/- mice were utilized due to their ability to develop severe vascular disease and acquire the elements of T2D after 16 weeks of a high fat diet (HFD). KGYY6 was administered by IV tail injection at a dose of 1mg/kg and compared to controls given vehicle only. Aortic en-Face analysis with Sudan IV stain demonstrated significant reduction in plaque in KGYY6 treated mice. Decreases in plaque area and changes in both smooth muscle and collagen measurement were additionally noted by sequential 5um aortic cross sections from the aortic valve leaflets into the ascending aorta. In-vitro analysis of CD3+CD4+CD40+ splenic cells demonstrated a reduction in inflammatory cytokine expression in response to KGYY6 treatment, specifically IL2, IFNγ, and IL17, which are potent cytokines in atherosclerosis. Western blot analysis performed on adipose and muscle tissue demonstrated an increased expression of the glucose transport protein GLUT 4, with corresponding glucose tolerance testing demonstrating increased glucose tolerance and improved insulin sensitivity with lowered plasma insulin level. KGYY6 normalizes the aberrant CD40/CD154 interaction, reducing inflammatory cytokines and regulating glucose, all together resulting in abrogating atherosclerosis.