Systemic Loss of FKBPL Uncovers Diabetes-Dependent Pathways of Myocardial and Vascular Injury

BACKGROUND: Impaired angiogenesis underpins cardiovascular disease, particularly in people with diabetes; however, molecular mechanisms are still poorly understood. This study aims to decipher the role of an emerging antiangiogenic protein, FKBPL (FK506-binding protein–like), on cardiac structure and function, vascular integrity, and inflammatory signaling in in vivo and in vitro models of diabetes. METHODS: In vivo, FKBPL transgenic mice ( fkbpl +/− ) were used to examine the metabolic and cardiovascular function and FKBPL-mediated mechanisms in streptozotocin-induced diabetes. In addition, comprehensive in vitro assessments of endothelial function and mechanisms were performed in normal/high-glucose and high/low-FKBPL conditions. RESULTS: Fkbpl +/− mice show signs of early cardiac remodeling (increased E/A ratio, P =0.047, and cardiomyocytes size, P =0.0018; reduced collagen deposition, P =0.013; col1a1 mRNA reduction, P =0.0028) and aberrant expression of cardiac vascular dysfunction proteins (ICAM-1 intercellular adhesion molecule 1, P <0.001, SIRT-1 sirtuin 1; P <0.001). Proinflammatory cardiac profile was prominent in fkbpl +/− murine hearts with increased protein expression of ICAM-1, IL (interleukin)-12p40, IL-15, IL-22, LIF (leukemia inhibitory factor), lipocalin-2, MMP (matrix metalloproteinase)-3/-9, periostin, serpin E1, and VCAM-1 (vascular cell adhesion molecule 1), which were decreased in diabetes. In diabetic mice with low FKBPL expression, glucose metabolism deteriorated, whereas vascular dysfunction improved. In normal glucose conditions, FKBPL knockdown in human aortic endothelial cells reduced VE-cadherin (vascular endothelial cadherin; P =0.0016) and impaired endothelial barrier ( P <0.001). In high-glucose conditions, endothelial FKBPL knockdown improved angiogenesis, however overexpression of FKBPL reduced angiogenesis by inhibiting the FGF (fibroblast growth factor) 2 and PDGF (platelet-derived growth factor) pathways ( P <0.001) and increasing proinflammatory pathways (TGF transforming growth factor-β, P <0.001; leukocyte migration, P =0.033; IL-7 signaling, P =0.039), by upregulating miR-29b-3p ( P =0.01) and miR-302b-5p ( P =0.03), likely via CD44. FKBPL-based peptide mimetic, AD-01 (1 nM), in high-glucose conditions, upregulated endothelial vcam1 and glut1 mRNA expression, independent of miR-302b-5p. CONCLUSIONS: FKBPL plays an important role in glucose metabolism, endothelial function, angiogenesis, cardiac inflammation and function, and could be explored as a therapeutic target of cardiovascular disease both in nondiabetes and diabetes settings using precision medicine approach.