Protective role of the DHCR24 enzyme in human coronary aortic endothelial cells — ASN Events
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Protective role of the DHCR24 enzyme in human coronary aortic endothelial cells (#83)

Kristine CY McGrath 1 2 , Xiao Hong Li 1 , Philip J Barter 1 , Kerry-Anne Rye 1 , Alison K Heather 1 2
  1. Heart Research Institute, Newtown, NSW, Australia
  2. Medical and Molecular Biosciences, University of Technology Sydney, Sydney, NSW, Australia

Background: Diabetes mellitus is associated with an approximately two to four fold times increased risk of cardiovascular events, as compared with control population. This increased risk is in part because diabetes increases inflammation, one of the main drivers of atherosclerosis. Recently it has been demonstrated that the enzyme 3β-hydroxysterol-Δ24 reductase (DHCR24), primarily known for its role in catalysing the final step in cholesterol synthesis, plays a role in protecting against inflammation, oxidative stress and apoptosis in a number of different cell types. Given that inflammation, oxidative stress and apoptosis are triggers for the development of endothelial cell dysfunction, a known early feature of atherosclerosis, we tested the hypothesis that DHCR24 may protect against human coronary artery endothelial cell (HCAEC) dysfunction.

Aim: To investigate the effects of silencing and increasing DHCR24 expression in HCAEC on inflammatory response, oxidative and endoplasmic reticulum stress, and apoptosis.

Methods: DHCR24 siRNA was used to silence DHCR24 expression. pcDNA3.1A(-)/ myc-His-LacZ vector was used to clone human DHCR24 cDNA. Gene expression changes were explored using Affymetrix microarrays and verified by real-time PCR. Oxidative stress was measured by hydroethidine staining. ER stress and mitochondrial membrane potential was determined by real-time PCR and flow cytometry, respectively. Apoptosis was measured by DNA fragmentation and Caspase 3/7 assays.

Results: Low DHCR24 expression in HCAEC increased inflammation, oxidative stress and apoptosis. The inflammation was dependent on an NADPH oxidase-mediated oxidative stress response and was independent of an effect on cholesterol synthesis. High DHCR24 expression protected HCAEC against TNF-α and H2O2-induced inflammation, oxidative stress and apoptosis.

Conclusion: Together, these results provide compelling evidence that DHCR24 may play a protective role in HCAEC by a mechanism independent of its role in cholesterol synthesis. This data opens up a new therapeutic avenue targeting DHCR24 levels for the treatment of diabetes-associated inflammation.