Indiana University-Purdue University Indianapolis (IUPUI) / Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of incretin
based therapeutics which aid in blood glucose management in Type II diabetes
mellitus (T2DM). Recent studies have demonstrated direct cardiovascular benefits
conferred by these agents including protection in ischemia and heart failure.
Despite these observations, human clinical trials fail to support improvements in
cardiovascular outcomes independent of glucose lowering effects in the T2DM
populations. Prior data from our lab demonstrate that obesity impairs GLP-1
associated increases in myocardial glucose uptake. However, the reasons for this
impairment/resistance to cardiac effects of GLP-1 in the setting of obesity remain
ill defined. This investigation tested the hypothesis that underlying differences in
the cardiac proteome and microRNA (miR) transcriptome could contribute to
distinct cardiac responses to ischemia and activation of GLP-1 signaling in the
setting of obesity.
To identify whether obesity modulated cardiac functional responses to GLP
1 related drugs, we first examined the effects of obesity on cardiac function, miR
transcriptome, and proteome in response to short duration ischemia-reperfusion
(I/R). We observed divergent physiologic responses (e.g. increased diastolic
volume and systolic pressure in lean, decreased diastolic volumes in obese) to
regional I/R in obese vs lean hearts that were associated with significant molecular
changes as detected by protein mass spectrometry and miR microarray. Molecular changes were related to myocardial calcium handling (SERCA2a, histidine-rich
Ca2+ binding protein), myocardial structure and function (titin), and miRs relating
to cardiac metabolism, hypertrophy, and cell death, including miR-15, miR-30,
miR-199a, miR-214. Importantly, these effects were modified differently by GLP-1
agonism in lean vs obese swine.
Additional studies investigated the functional effects of 30 days of treatment
with the GLP-1 analogue liraglutide on a model of slowly-developing, unrelieved
coronary ischemia. Liraglutide failed to reduce infarct size or collagen deposition.
However, analysis of left ventricular pressure-volume relationships support that
liraglutide improved diastolic relaxation/filling, load-dependent indices of cardiac
function, and cardiac efficiency in response to sympathetic stimulation in obese
swine. Taken together, these findings support that miR and proteomic differences
underlie distinct changes in functional cardiac responses to I/R and pharmacologic
activation of GLP-1 signaling in the setting of obesity.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10980 |
| Date | 13 May 2016 |
| Creators | Sassoon, Daniel Jay |
| Contributors | Tune, Johnathan, Mather, Kieren |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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