Blake Hill PhD.
Abstract
Rationale: Mitochondrial dysfunction is one of several factors that drives the development of vascular endothelial dysfunction in type 2 diabetes (T2DM). In endothelial cells from T2DM patients, mitochondrial networks are highly fragmented, with increased expression of mitochondrial fission protein 1 (Fis1). However, whether manipulation of Fis1 expression and activity in human resistance arterioles (microvessels) from patients with T2DM alters endothelial function remains unknown and is critical to determining if Fis1 inhibition could be a viable strategy for reducing microvascular risk in T2DM.
Objective: To determine Fis1’s function in regulating human microvascular endothelial function in both health and in the setting of T2DM and to derive and test a novel, first-in-class Fis 1 inhibitor forits ability to affect human microvascular endothelial function.
Participants: 71 healthy individuals and 33 individuals with T2DM were recruited for gluteal adipose pad biopsies or for discarded subcutaneous adipose tissues to be recovered from surgical procedures.
Methods and Results: Molecular suppression of Fis1 reversed impaired endothelium-dependent vasodilation of vessels from T2DM patients, as well as healthy human vessels exposed to high (33 mM) or low (2.5 mM) glucose, while preserving NO bioavailability and improving endothelial cell layer integrity. Conversely, overexpression of Fis1 in healthy vessels impaired vasodilation and increased mitochondrial superoxide, suggesting a causative role. Application of a novel and specific Fis1 inhibitor, pep213, improved endothelium-dependent vasodilation of vessels from T2DM patients, as well as healthy vessels exposed to high glucose or Fis1 overexpression, by improving NO bioavailability and decreasing excess mitochondrial ROS generation. Pep213's specificity was confirmed through multiple techniques including a 1.85 Å crystal structure. Additionally, pep213 hindered Fis1 binding to fission enzyme Drp1. These findings suggest excessive mitochondrial fragmentation underlies endothelial dysfunction, offering a therapeutic pathway for diabetic microvascular disease via Fis1 inhibition.
Conclusions: These data support that excessive mitochondrial fragmentation drives endothelial vessel dysfunction and supports a potential novel therapeutic route for treating diabetic microvascular disease through pharmacological inhibition of Fis1.
When: April 11, 2025
Where: North Classroom 1130
Time: 11:00 am - 12:00pm