MiR-433-3p Inhibition Alleviates Increased Endothelial Cell Permeability in Diabetes

Hypothesis: miR-433-3p is a potential therapeutic target to reduce the excess endothelial permeability seen in peripheral skeletal muscle of diabetes. Background: Peripheral arterial disease (PAD) is a complication of systemic atherosclerosis that results from occlusions in the large arteries of the leg(s). Though best known as a large vessel disease, patients with PAD also have microvascular disease including excess vascular permeability. Patients with diabetes have an increased risk to develop PAD and more severe symptoms compared to nondiabetic patients with PAD patients. MicroRNAs (miRNAs) are a class of small, non-coding RNAs that modulate gene expression by targeting mRNA post-transcriptionally. Methods: Age-, sex-, and risk factor-controlled plasma samples were selected from a PAD biobank. Plasma samples from non-PAD controls, patients with intermittent claudication (IC), or with critical limb ischemia (CLI), with or without diabetes, were selected and miR-433-3p expression was assessed by RT-qPCR. MiR-433-3p expression was analyzed in human ECs after high glucose (HG) (25 mM) or osmolar control (25 mM Mannitol) treatment under normoxia or hypoxia-serum starvation. ECs were also treated with miR-433 inhibitor or negative control. Endothelial vascular permeability, angiogenesis, and cell viability/survival were tested. Vascular permeability by Evans Blue Dye (EBD) was measured in High Fat Diet (HFD) mice versus C57BL/6 mice treated with 100 μM hind-limb, intramuscular injections of miR-433-3p inhibitor, or scramble. Results: Plasma levels of miR-433-3p were elevated in CLI patients with diabetes. In human ECs, miR-433-3p expression was also elevated after high glucose treatment. Endothelial barrier function was impaired after HG, which was restored by miR-433 inhibition. Similarly, miR-433-3p inhibitor improved angiogenesis and cell survival after HG treatment in ECs. HFD mice demonstrated an increased vascular permeability compared to C57BL/6 mice which was attenuated by miR-433-3p inhibition. Conclusion: These data suggest miR-433-3p’s effect on vascular permeability which may contribute to the very poor clinical course seen in PAD and DM. Improved EC permeability with miR-433-3p inhibition may improve skeletal muscle perfusion and create a novel approach for patients with PAD, diabetes, or both. NIH 5R01HL150003-03 (BHA) and AHA CDA932159 (AK) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.