The Non-Genomic Effects of Anti-Diabetic Drugs on Cells of the Cardiovascular System
University of Wales Institute Cardiff
MetadataShow full item record
Thiazolidinediones (TZDs) are a class of oral anti-hyperglycaemic agents receiving continued attention regarding potential implications of TZD therapy on risk of negative cardiovascular outcomes among patients with type 2 diabetes mellitus (T2DM). Recent studies have provided valuable insight into the mechanisms underlying these effects however much remains to be elucidated. In our current investigation of non-genomic effects of thiazolidinediones on cells of the cardiovascular system we employ methods adapted from Shang and Caddy et al. to further investigate TZD induced ER stress and upregulation of UPR pathways in THP-1 monocytic cells by qualitative and quantitative analysis of XBP-1 spliced variants in thapsigargin, rosiglitazone (1 and 10μM) and pioglitazone treated cells following each sequential dose; providing valuable insight in the ongoing investigation into thiazolidinedione associated effects on cells of the cardiovascular system. THP-1 monocytic cells were maintained in culture and treated with DMSO, thapsigargin (100nM), rosiglitazone (1 and 10μM) or pioglitazone (3μM) for a period of 14 days with sample collection at each passage. RNA yields were checked for purity and converted to cDNA for qualitative PCR and gel electrophoresis of XBP-1 spliced variants. XBP-1 activation was quantified by densitometric analysis and subject to statistical evaluation. Findings from this and concurrent investigations by Kate Morgan and Suzanne Dent (CMET BSc 2012) suggest that physiologically representative 1μM rosiglitazone-induced UPR activation was neither sustained nor excessive to induce a proapoptotic state upon sequential dosing over a 14 day investigation period; however an observed increase in apoptotic cell death from day 12 onwards raises concerns regarding the effect of treatment with 1μM rosiglitazone over a more prolonged time period. In contrast physiologically representative 3μM pioglitazone treatment induced a highly significant increase in apoptotic cell death throughout the 14 day investigation period (P<0.001), similar to that observed with high-dose 10μM rosiglitazone treatment which was incidentally shown to induce sustained and/or excessive UPR activation and progression to a proapoptotic state . As pioglitazone remains licensed for use in the treatment of type 2 diabetes mellitus these findings highlight an urgent requirement for further elucidation of the molecular mechanisms unpinning PPARγ-independent effects of pioglitazone treatment on cells of the cardiovascular system.
Showing items related by title, author, subject and abstract.
Morgan, Kate (University of Wales Institute Cardiff, 2012)The thiazolidinediones (TZDs) are a class of drugs used in the treatment of Type 2 Diabetes Mellitus (T2DM). TZDs are ligands of the transcription factor Peroxisome Proliferator-Activated Receptor gamma (PPAR) and are ...
Conjugated linoleic acid, but not rosiglitazone and pioglitazone increase apoptosis/reduce viabillity in a monocytic cell line Klimach, Stefan (Cardiff Metropolitan University, 2011)Thiazolidinediones (TZDs) are a class of oral chemotherapeutics used in the treatment of type 2 diabetes mellitus (TTDM). TZDs improve insulin sensitivity in TTDM by modulating the transcriptional effects of peroxisome ...
Willis, Gareth (Cardiff Metropolitan University, 2011)BACKGROUND: Conjugated linoleic acid (CLA) has been established as a natural peroxisome proliferator activated receptor (PPAR-y) ligand. Recent studies have explored the possible health benefits associated with CLA for ...