Abstract:
PURPOSE:To evaluate whether aleglitazar (Ale), a dual PPARα/γ agonist, has additive effects on myocardial protection against ischemia-reperfusion injury. METHODS:Human cardiomyocytes (HCMs), cardiomyocytes from cardiac-specific PPARγ knockout (MCM-PPARγ (CKO) ) or wild type (MCM-WT) mice were incubated with different concentrations of Ale, and subjected to simulated ischemia-reperfusion (SIR) or normoxic conditions (NSIR). Cell viability, apoptosis and caspase-3 activity were determined. HCMs were transfected with siRNA against PPARα (siPPARα) or PPARγ (siPPARγ) followed by incubation with Ale. PPARα/γ DNA binding capacity was measured. Cell viability, apoptosis and levels of P-AKT and P-eNOS were assessed. Infarct size following 30 min coronary artery occlusion and 24 h reperfusion were assessed in WT and db/db diabetic mice following 3-day pretreatment with vehicle, Ale or glimeperide. RESULTS:Ale (at concentrations of 150-600 nM) increased cell viability and reduced apoptosis in HCMs, MCM-WT and MCM-PPAR (CKO) exposed to SIR. In HCM, the protective effect was partially blocked by siPPARα alone or siPPARγ alone, and completely blocked by siPPARα+siPPARγ. Ale increased P-Akt/P-eNOS in HCMs. P-Akt or P-eNOS levels were decreased when PPARα alone, PPARγ alone and especially when both were knocked down. Peritoneal GTTs revealed that db/db mice had developed impaired glucose tolerance and insulin sensitivity, which were normalized by Ale or glimepiride treatment. Ale, but not glimepiride, limited infarct size in both WT and diabetic mice after ischemia-reperfusion. CONCLUSIONS:Ale protects against myocardial apoptosis caused by hypoxia-reoxygenation in vitro and reduces infarct size in vivo.
journal_name
Cardiovasc Drugs Therjournal_title
Cardiovascular drugs and therapyauthors
Qian J,Chen H,Birnbaum Y,Nanhwan MK,Bajaj M,Ye Ydoi
10.1007/s10557-016-6650-9subject
Has Abstractpub_date
2016-04-01 00:00:00pages
129-41issue
2eissn
0920-3206issn
1573-7241pii
10.1007/s10557-016-6650-9journal_volume
30pub_type
杂志文章abstract::Despite the fact that beta blockers were introduced into clinical practice 25 years ago, new beta blockers with differing kinetic and dynamic profiles continue to be developed and marketed. This overview assesses some of the more extensively studied agents from the point of view of proof of utility and the validity of...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,已发布勘误
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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journal_title:Cardiovascular drugs and therapy
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