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Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy
- Source :
- Oxidative Medicine and Cellular Longevity, Vol 2020 (2020)
- Publication Year :
- 2020
- Publisher :
- Hindawi, 2020.
-
Abstract
- Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.
- Subjects :
- 0301 basic medicine
Cardiac function curve
Aging
Small interfering RNA
Article Subject
Activating transcription factor
030204 cardiovascular system & hematology
Pharmacology
medicine.disease_cause
Biochemistry
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Fibrosis
Medicine
Myocyte
QH573-671
business.industry
Cardiac muscle
Cell Biology
General Medicine
medicine.disease
030104 developmental biology
medicine.anatomical_structure
business
Cytology
Oxidative stress
Subjects
Details
- Language :
- English
- ISSN :
- 19420900
- Database :
- OpenAIRE
- Journal :
- Oxidative Medicine and Cellular Longevity
- Accession number :
- edsair.doi.dedup.....6200123d4eb4b3bdbe1056f49ea15821
- Full Text :
- https://doi.org/10.1155/2020/9187065