The primary cause of death in diabetes is heart failure. Growing evidence suggests that remodeling of the physical microenvironment of the heart drives cardiomyocyte pathology, independent of hypertension and coronary artery disease. Several studies have thus far provided evidence that the extracellular matrix (ECM) changes with diabetic peripheral complications by vascular obstruction and fibrotic hypertension. Rather than a secondary phenomenon, our in vitro data implicates fibroblast derived ECM as a direct regulator of cardiomyocyte insulin sensitivity. Using published methods, we observe that ECM derived from plated primary neonatal cardiac fibroblasts is structurally altered when produced in low- (5mM) versus high-glucose (25mM), with respect to density indicative of collagen crosslinking (Aniline blue staining) and increased stiffening (Atomic Force Microscopy). Most importantly, plating primary cardiomyocytes on high-glucose (vs. low-glucose) fibroblast derived matrix reduces insulin sensitivity (Akt/PKB phosphorylation). We also observe reduced Focal Adhesion Kinase (FAK) activation and c-Jun N-terminal kinase (JNK) inactivation within this in vitro platform; pathways which have been shown to regulate insulin sensitivity via integrin binding to ECM proteins. The cardiac fibroblast derived matrix model serves as a high throughput in vitro platform, which we have thus far used to establish the direct relationship between ECM deposition and insulin sensitivity. Future work will use the platform to dig into the underlying mechanisms implicating ECM remodeling and sensing in the pathogenesis of diabetic cardiomyopathy and heart failure.


S. Nieuwoudt: None. X. Wang: None. S. Senapati: None. P. Park: None. S. Senyo: None.


Case Western Reserve University (RES221997); Wallace H. Coulter Foundation; National Heart, Lung, and Blood Institute (T32HL134622-02)

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