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DiaComp Funded Abstracts Pilot & Feasibility Funding Programs

Pilot & Feasibility Program Application Abstract

Wnt/G3BP1 Signaling In Arterial Calcification: Mitigation by PADI Inhibition
Dwight Towler   (Dallas, TX)
Diabetes increasingly afflicts our aging, dysmetabolic populace. While impacting every system, the cardiac and renovascular consequences of long-standing hyperglycemia are major contributors to frailty, morbidity, and mortality of type II (T2D) diabetes. Arterial disease progresses for several years prior to disease recognition and intervention – and, with tissue sclerosis, globally diminish capacity to withstand further ischemic, metabolic, infectious, traumatic or mechanical insults. Arterial calcification – a consequence of diabetes and a key contributor to vascular stiffness -- has emerged as a risk factor for ischemic stroke, dementia, and lower extremity amputation. In our preclinical studies of diet-induced T2D, we first that osteogenic Msx-Wnt signals are important in diabetic vasculopathy. We discovered that LRP6, a Wnt co- receptor best known in canonical signaling, limits noncanonical vascular smooth muscle (VSM) Wnt activities that drive arteriosclerosis. This occurs via protein arginine methylation relays. Arginine methylome analysis of intact and LRP6-deficient primary VSM cells have identified new noncanonical Wnt signals – including one mediated by G3BP1 (Ras GTPase-activating protein binding-protein 1). Others recently demonstrated that genetic variation in G3BP1 impacts the extent of cardiovascular disease in humans. Strategies that reduce G3BP1 function are predicted to reduce arteriosclerotic disease, thereby improving distal tissue perfusion. No therapies currently target G3BP1; however, in our studies of methylarginine metabolism, we discovered that protein arginine deminases (PADIs), are co-activators of G3BP1 - dependent noncanonical Wnt signaling in VSM. PADI inhibitors have been developed that limit neutrophil activation in arthritis. We test whether the prototypic PADI inhibitor Cl-amidine reduces arterial osteogenic mineralization, inflammation, and stiffness in the LDLR-/- mouse model of diet-induced diabetes. We generate VSM G3BP1-deficient mice to determine cell-autonomous roles to arteriosclerotic calcification. Our pilot study assesses whether targeting PADI-dependent Wnt/G3BP1 pathways can mitigate arterial calcification as a complication of T2D -- consistent with the DiaCOMP translational research mission.
Data for this report has not yet been released.