PPAR-γ activation fails to provide myocardial protection in ischemia and reperfusion in pigs
Open accessAbstract
Peroxisome proliferator-activated receptor (PPAR)-γ modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-γ activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-γ activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both α-tocopherol and thiazolidinedione moieties, whether PPAR-γ activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg·kg−1·day−1), rosiglitazone (3 mg·kg−1·day−1), or α-tocopherol (73 mg·kg−1·day−1, equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-γ, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or α-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an α-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-γ activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its α-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-γ activation in the heart.
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Studies in nondiabetic rats have shown a positive benefit of TZD treatment upon ischemia/reperfusion, although this has not been shown to be true for other models such as pigs.
“Studies in nondiabetic rats have also shown a positive benefit of TZD treatment upon ischemia/reperfusion (158, 176, 390), although this has not been shown to be true for other models such as pigs (380).”
From Cardiac remodeling in obesity (2008) · cites this paper as [380]
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Abel, E. D., Litwin, S. E., & Sweeney, G. (2008) · Physiological Reviews · doi:10.1152/physrev.00017.2007 · Cited by 736 · see citing works
- Authors
- Xu, Y., Gen, M., Lu, L., Fox, J., Weiss, S. O., Brown, R. D., Perlov, D., Ahmad, H., Zhu, P., Greyson, C., Long, C. S., & Schwartz, G. G.
- Affiliations
- Veterans Health Administration (US)
- Denver VA Medical Center (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2005-03
- Volume
- 288
- Issue
- 3
- Pages
- H1314-H1323
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC3633522
- OpenAlex
- W2154718420
- Cited by
- 49
- References
- 62
- Citations by year
- 2025: 1 · 2021: 2 · 2020: 1 · 2018: 2 · 2017: 3 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Heart, Lung, and Blood Institute (R01HL068606, HL68606, R56HL049944, R01HL049944, HL49944)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- PPARγ activation, myocardial ischemia-reperfusion injury, troglitazone, rosiglitazone, alpha-tocopherol, thiazolidinediones, cardiac contractility, lactate utilization, inflammatory cytokines, regional myocardial ischemia, species differences, porcine model
- MeSH terms
- Rosiglitazone, Troglitazone, Animals, Antioxidants, Chromans, Coronary Circulation, Energy Metabolism, Fatty Acids, Nonesterified, Female, Hypoglycemic Agents, Male, Myocardial Contraction, Myocardium, RNA, Messenger, Myocardial Reperfusion Injury, Cytokines, Ventricular Function, Left, alpha-Tocopherol, Sus scrofa, Thiazolidinediones, PPAR gamma
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