Diabetes mellitus (DM) is a key public health problem that contributes to an elevated risk of cardiovascular (CV) events. Currently, limited treatments exist to reduce CV risk in DM patients. The molecular mechanisms linking DM, insulin resistance and CV disease remain incompletely understood. Defining the signaling pathways leading to endothelial dysfunction holds promise to develop novel therapies for vascular protection in DM. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been individually associated with metabolic diseases. We have shown that altered mitochondrial dynamics and ER stress are associated with endothelial dysfunction in the vasculature of DM patients; however, whether perturbation of organelle interactions contributes to endothelial dysfunction and insulin resistance in the vascular endothelium is unknown. Our preliminary data using a novel technique to study freshly isolated endothelial cells from patients, links aberrant ER stress activation to mitochondrial dysfunction and vascular insulin resistance. Additionally, we have found DM is associated with a diminished expression of a key protein involved in the integrity of ER and mitochondria connections. We hypothesize that ER stress activation is associated with mitochondrial and vascular dysfunction in human DM. Furthermore, we hypothesize that ER stress inhibition will restore ER-mitochondrial connections, which would be critical to restore mitochondrial and endothelial function in DM. We propose to conduct a set of studies designed to gain evidence of the functional importance of ER-mitochondria interactions in mediating endothelial dysfunction in human DM. We will manipulate ER stress activation 1) pharmacologically (TUDCA) and 2) genetically (siRNA knockdown) to determine whether inhibiting its activation restores endothelial and mitochondrial function. In addition, we will study the expression of proteins involved in the interaction between ER-mitochondria and relate cell findings of MAM integrity to the in vivo measures of vascular function. Finally, we will seek to gain early evidence of a beneficial vascular effect of inhibiting ER stress by conducting a randomized, double-blinded crossover study assessing the impact of TUDCA on vascular function, endothelial cell phenotype, and MAM integrity. The proposed study will add additional mechanistic insight and could lead to refined therapies to protect the vasculature and reduce vascular disease in DM.
|Program type||Career Development Award|
|Effective start/end date||04/01/2019 → 09/15/2019|