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The AMPK Agonist PT1 and mTOR Inhibitor 3HOI-BA-01 Protect Cardiomyocytes After Ischemia Through Induction of Autophagy
- Source :
- Journal of Cardiovascular Pharmacology and Therapeutics. 21:70-81
- Publication Year :
- 2015
- Publisher :
- SAGE Publications, 2015.
-
Abstract
- Myocardial ischemia has become one of the main causes of sudden cardiac death worldwide. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R)-induced damage. A novel small molecule compound 2-Chloro-5-[[5-[[5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl]methylene]-4,5-dihydro-4-oxo-2-thiazolyl]amino]benzoic acid (PT1) has been previously shown to specifically activate 5′-adenosine monophosphate-activated protein kinase (AMPK). Because AMPK activation effectively induces autophagy, we tested the protective efficacy of PT1 on cardiomyocytes after oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Mouse neonatal cardiomyocytes were treated with PT1 after OGD/R. 3-[4-(1,3-benzodioxol-5-yl)-2-oxo-3-buten-1-yl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (3HOI-BA-01), a novel small compound showing potent inhibitory effect on mammalian target of rapamycin (mTOR) activation, was also tested for its cardioprotective effect, based on the established relationship between mTOR signaling and autophagy. Cell survival and autophagy-related signal pathways were examined after treatment with these agents. Our data indicate that both PT1 and 3HOI-BA-01 enhance cell survival after OGD/R. As expected, both PT1 and 3HOI-BA-01 induced autophagy in cardiomyocytes through activating AMPK pathway and inhibiting mTOR signaling, respectively. Induction of autophagy by PT1 and 3HOI-BA-01 was responsible for their cardioprotective effect, since inhibition of autophagy abolished the protective efficacy. Furthermore, simultaneous administration of PT1 and 3HOI-BA-01 profoundly upregulated autophagy after OGD/R and significantly promoted survival of cardiomyocytes. In vivo administration of PT1 and 3HOI-BA-01 in a murine myocardial (I/R injury model remarkably reduced infarct size and induced autophagy. Taken together, our research suggests that PT1 and 3HOI-BA-01 could be promising therapeutic agents for myocardial ischemia.
- Subjects :
- Male
0301 basic medicine
Agonist
medicine.medical_specialty
Indoles
medicine.drug_class
Myocardial Infarction
Apoptosis
Myocardial Reperfusion Injury
AMP-Activated Protein Kinases
Pharmacology
Mice
03 medical and health sciences
Downregulation and upregulation
Internal medicine
Autophagy
medicine
Animals
Myocytes, Cardiac
Pharmacology (medical)
Benzodioxoles
Protein kinase A
Protein Kinase Inhibitors
Cells, Cultured
PI3K/AKT/mTOR pathway
business.industry
TOR Serine-Threonine Kinases
RPTOR
AMPK
Adenosine
Cell Hypoxia
meta-Aminobenzoates
Mice, Inbred C57BL
Oxygen
Disease Models, Animal
Thiazoles
Glucose
030104 developmental biology
Endocrinology
Animals, Newborn
Cytoprotection
Cardiology and Cardiovascular Medicine
business
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 19404034 and 10742484
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Journal of Cardiovascular Pharmacology and Therapeutics
- Accession number :
- edsair.doi.dedup.....5b64e4b670b3f2db10a15fa4cee3fc11